The Dominion War, a costly struggle pitting the combined Federation, Klingon and Romulan forces against the Cardassian Union and Breen Confederacy as puppets of the Gamma Quadrant power named only the Dominion, ends. A costly war that has seen the near-collapse of the Cardassian Union and the overall 10-year setback of the Klingon Empire leaves the Federation and Romulan Empire as the contending superpowers in the Alpha-Beta Quadrants.

Following the war, Bajor is admitted into the Federation, long-overdue in the eyes of many.

After a resurgence of the threat of parasitic aliens (TNG: Conspiracy) which are learned to be know as the Kurl, it is discovered that these parasites are a genetically altered abnormality of the Trill symbiont, and a genocide was attempted on the Kurl by the Trill nearly five thousand years before. Civil unrest on Trill leads to terrorist acts which decimate the secretly abundant race of symbionts. Dr Julian Bashir develops a stable procedure for separating symbionts from hosts and allowing the host to live; as a result of the terrorist bombings, it is declared that no new joinings are to occur on Trill, to allow the symbionts to reproduce and grow their species. All current hosts are offered the choice of allowing their symbionts to be separated medically to return to the spawning pools, or to continue existence with their symbiont until the host's death, at which time the symbiont will be returned to the pools.

Starfleet launches the Luna-class Deep Space Explorer, in an effort to return to the Federation's primary mission of exploration.

Tezwa, an independent system on the edge of Klingon space, challenges the Klingon Empire and takes a Klingon diplomatic delegation hostage. In response, the Klingons decimate the planet's surface before being destroyed with nadion-pulse cannons. The Federation Starfleet conquers and occupies Tezwa following the Klingon fleet's destruction, ostensibly to avoid war. In reality, the Federation President ordered the contest to conceal from the Klingons the cannons' Federation origin. Tezwan Prime Minister Kinchawn is deposed. IN the ensuing insurgency, thousands of Starfleet officers, Federation civilian aide workers, and innocent Tezwans are killed in Federation occupation of Tezwa.

Starfleet uncovers the nadion cannons' origins and the role of the Tezwan government in covering them up; the Federation Starfleet is ordered off of Tezwa by Tezwan Prime Minister Bilok. Federation President Min Zife of Bolarus resigns from office, along with Chief of Staff Koll Azernal of Zakdorn and Federation Secretary of Military Intelligence Nelino Quafina of Antede III. Their resignations are forced upon them by Starfleet Admiral William Ross of Earth. The three are subsequently assassinated in secret by the rogue cabal known as Section 31. The general public remains unaware of President Zife's true reason for resignation.

Federation Councillor Ra'ch B'ullhy of Damiano serves as President Pro-Tempore of the United Federation of Planets for one month following Zife's resignation. The Federation Council calls a special election, and Governor Nanietta Bacco of Cestus III defeats Federation Special Emissary Arafel "Fel" Pagro of Ktar. Lieutenant Governor Yrolla Gari becomes Governor of Cestus III following Nan Bacco's election as President of the Federation.

In a failed plot to destroy the Federation, Romulan Praetor Shinzon is defeated at the Battle of the Bassen Rift, leaving Senator Tal'aura to take the reigns as the new Praetor, with the support of Fleet Commander Tomalak. The resulting spatial catastrophe becomes a permanent marker in space referred to by the Romulans as "The Great Bloom." Commander Donatra of the Warbird Valdore openly opposes the new Praetor, and begins a rebellion backed by the strength of the Romulan Third and Fifth Fleets. Additionally, the Reman people openly demand a continent on Romulus and reparations for hundreds of years of slavery. A Romulan blockade of Remus is the Praetor's reply, as well as cutting food and medical supplies to the sister planet. The Federation, represented by Federation Starfleet Captain William T. Riker of Earth, commanding officer of the USS Titan, attempts to mediate power-sharing talks between the numerous Romulan and Reman factions. An agreement is eventually reached whereby Remus is made a protectorate of the Klingon Empire and the Reman people allowed to settle on a Romulan continent.

On the verge of collapse, the Cardassian Union begins a joint effort with Federation scientists known as the Andak project, intended to restore agricultural production to the Union's fledgling democratic government.

Open civil war within the Romulan Empire; a new faction emerges, called the Imperial Romulan State, under the leadership of Admiral Donatra.

After a failed attempt at Reman colonization of a continent on Romulus, the Remans are eventually relocated to the Klingon planet of Klorgat VII. Klingon and Romulan forces continually come to blows as Klingon ships patrol much of the Romulan Star Empire.

At a diplomatic conference, the Klingon Empire agrees to end its expansionist policies.

The Federation begins providing material and humanitarian aid to the devastated Romulan Star Empire, and attempts to facilitate negotiations for the re-establishment of permanent government.

The Alpha and Beta Quadrants suffer an all-out offensive by the Borg, in which the Borg's goal is not assimilation but the total annihilation of the Federation and its allies. The galaxy's only hope is the Caelier, a newly discovered race who are revealed to be the true source of the Borg millennia before. Although reluctant, the Caeliar are convinced to set aside their xenophobic ways and wage their own battle with the Borg. They end the threat by dissolving the true source of the Collective: the original Caeliar at the heart of the Borg Queen. Trillions of Borg are freed in this action and accepted into the Caeliar gestalt. The Caelier and the former drones ascend into another dimension, leaving behind sixty-three billion casualties across the Federation, Klingon and Romulan empires, including the destruction of Deneva and Risa, massive losses on Vulcan, Andor, and Qo'Nos, the eradication of over half the Klingon High Council and the loss of over forty percent of Starfleet. (See: Star Trek Destiny novel series)

Riots break out in the city of New Samarkand on Alpha Centauri, precipitated in part by the mass influx of refugees from the Borg Invasion.

Massive rebuilding efforts begin among all the Alpha Quadrant powers. In the Federation, hundreds of millions of refugees need to be found and relocated among those member worlds that withstood the brunt of the Borg's attack. The Klingon Empire comes under attack by a race known as the Holy Order of the Kinshaya, a long and bitter enemy along the Klingon's southernmost border. The Kinshaya take Krios and H'atoria, but are found to be using a combination of Breen and Romulan weaponry in their attacks. A Klingon attempt to re-capture Krios is met by Breen, Gorn and Tzenkethi ships aiding the Kinshaya. Krios is retaken, but it is soon learned through formal declaration that the Romulan Empure, Breen, Kinshaya, Tzenkethi, Gorn and Tholians have allied to create the Typhon Pact, an alliance powerful enough to rival the Federation/Klingon alliance. In response, the Federation and Klingons revisit the Khitomer Accords, inviting alliances with the Cardassian Republic, Ferengi Alliance, Talarian Republic and Imperial Romulan State.

Praetor Tal'aura captures Admiral Donatra, the latter committing suicide in captivity. Not long after, Tal'aura suffers a brain aneurysm due to a genetic disease. The Romulan Empire is reunited under the new Praetor, Gell Kamemor.

The Andorian government is also in a time of civil crisis; decades of dwindling reproductive rates are coming to a head, as the Andorian physiology and genetic disposition toward four sexes has begun to reduce fertility windows in Andorians to very short periods of their lives. A proposal is made to genetically engineer Andorian genomes into a two-sex biology, in order to allow the race to thrive. Many are worried that the research into genetic engineering will cause the Andorians to lose their cultural identity and this fear has, in some cases, led to a strong anti-Federation feeling and the belief that all non-Andorians should be expelled from the planet. Despite efforts by Federation diplomats to work with the Andorian government, a vote of no confidence is initiated against their pro-Federation presider and a referendum shows that a significant but not overwhelming majority of Andorians wish to secede from the Federation. The Andorians resign their Federation membership and make approaches to the Tholians to assist with their research in keeping their culture intact and ending their reproductive crisis.