The 24th century, defined in the calendar of Earth as being from 2301 until 2400, was a period of great conflict between the various races and organizations of the Milky Way Galaxy. The Federation made contact with several powerful new races such as the Borg, the Dominion and the Cardassian Union, all of whom attacked the Federation on several occasions. The Romulan Star Empire entered a fifty year isolation, from which they emerged far stronger than before. The Borg attempted to assimilate Earth twice, first in 2366 and again in 2373. The latter year also saw the beginning of the Dominion War, which ended in 2375, with the major powers of the Alpha and Beta Quadrants joining together to defeat the Dominion.
- 2311: After the Tomed Incident with the Romulan Star Empire, the Federation signs the Treaty of Algeron, promising no research into or use of any cloaking devices.
- 2344: At the Battle of Narendra III, the Federation vessel USS Enterprise-C defends a Klingon colony against Romulan attackers. Being regarded as an honorable act, the incident cements the Federation-Klingon alliance.
- 2364: A subtle attempt by neural parasites to take full control of Starfleet and to prepare for an all-out invasion of the Federation is discovered and thwarted.
- 2367: After making first contact with the Borg in 2365, a Borg cube attacks the Federation but is destroyed in Earth orbit after the Battle of Wolf 359. Later that year, Klingon Chancellor K'mpec is killed and succeeded by Gowron. His position is quickly challenged but eventually affirmed in the brief Klingon Civil War against the Romulan-influenced, but ultimately inferior, House of Duras.
- 2369: The Bajoran Wormhole is discovered, representing a secure link between the Alpha- and Gamma Quadrants.
- 2372: After the Dominion and the Founders were discovered in the Gamma Quadrant in early 2371, the Federation condemns an attack by the Founder-inflitrated Klingon Empire on the Cardassian Union. A few months later, a Founder-Changeling bombs the Antwerp Conference between the Federation and the Romulans, giving rise to an attempted but failed coup d'état against Federation President Jaresh-Inyo. Near the end of that year, the Federation's and Klingon's old dispute over the Archanis sector escalates, leading to the Klingon's withdrawal from the Khitomer Accords.
- 2373: After the Founder-infiltration of the Klingon Empire is discovered and the Cardassian Union joins the Dominion, the Khitomer Accords are re-instated. In the midst of these events another Borg cube attacks the Federation, but is destroyed near Earth at the Battle of Sector 001. Later that year, the Dominion conquers Deep Space 9, igniting the Dominion War against the Federation-Klingon alliance.
- 2374: After loosing Deep Space 9 to the alliance again, the Dominion conquers Betazed. Later that year, the Romulan Star Empire turns the tide of the conflict as it declares war against the Dominion.
- 2375: The Breen Confederacy allies with the Dominion and launches an attack on Starfleet Headquarters on Earth. Shortly after, Gowron is killed and Martok becomes the new Klingon Chancellor. Near the end of that year, with the help of the Cardassian Rebellion, the alliance manages to repel the Dominion forces, finally capturing Cardassia Prime and ending the Dominion War with the Treaty of Bajor.
- 2376: The Cardassian Union begins to form a democratic government led by elected Castellan Gerim Ertal. The Federation begins providing materiel and humanitarian aid to Cardassia. Betazed opposes provision of aid. Fearful of the Gorn's repositioning of fleet resources along their own borders, the Klingon Empire focus much of their rearming efforts along the borders closest to Gorn space, both sides instigating a Cold War between them. The Klingon's losses during the war and the Federation's expected intervention are all that prevent open war.
- 2377: The USS Voyager returns to the Alpha Quadrant, delivering a crippling blow to the Borg Collective by destroying a Transwarp hub and introducing a debilitating pathogen to the Collective.
- 2379: The Romulan Star Empire is taken over by Praetor Shinzon as the head of a Reman coup d'état. After a false peace offer to the Federation, Shinzon is killed in his attempt to wipe out all life on Earth with thalaron radiation. Shinzon's deposition creates disarray within the Empire. Shortly after, the Federation begins talks with the new Romulan government. The Tholian Assembly formally recalls their ambassador from Romulus in response to growing political unrest within the Romulan Empire.
- 2380: 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. A weakened Romulan State allows the Klingon Empire to instigate several border conflicts as the Empire seeks to expand into systems formerly annexed from them by the Romulans in centuries past.
- 2385: The Klingon Empire recovers from its losses during the Dominion War. The threat of intervention by the Federation is now all that prevents a Klingon-Gorn War.
- 2386: Several skirmishes occur between Klingon and Gorn starships in the region between the two powers, as each seeks to expand their borders into unclaimed space. The Federation lodges official notices of disapproval to the Klingon and Gorn embassies.
- 2387: The Metrons contact the Federation, and request for a diplomatic envoy to visit them. After a tense 'test' undergone by the crew of the USS Endeavour, diplomatic contact is not continued.
- 2388: The Klingon's refusal to assist in providing aid to the Romulan Empire strains the relationship with the Federation. The Klingon-Federation relationship is thought to be almost as unsteady as it was before the Klingons withdrew from the Khitomer Accords in 2372. Several minor skirmishes are reported along the Tholian-Federation border as a result of increased Starfleet and civilian operations in the region. Starfleet's 11th Fleet assigns a number of ships to the border regions, and assigns Captain Mark Anderson to oversee Tholian border operations.