A major war between the Federation Alliance and the Dominion.
The Dominion, a vast power ruled by the shapeshifting Founders from the Gamma Quadrant, came into contact with the Alpha Quadrant through the Bajoran wormhole. Suspicion grew as the Founders' hostility to solids became clear, and Starfleet struggled to find a way to prepare for a conflict that Sisko had been warning about.
The war began in earnest in 2373 when the Cardassian Union joined the Dominion. Early battles went badly for the allies, and Deep Space Nine fell to the Dominion for a time. The Federation, Klingon Empire and eventually the Romulans formed an alliance, and fought a series of large engagements, including Sisko's plan to bring in the Romulans and the retaking of the station. The Breen also changed the balance by joining the Dominion.
The war ended in 2375 after Cardassia rose in rebellion and the allies pressed through to its homeworld. The final battle, a peace treaty, and the Founders' defeat left millions dead and several worlds in ruins. Sisko, Kira, Odo, Martok, Worf, Garak, Damar and Weyoun are among the central figures of this conflict.