Misanthropic Dr. John Becker runs a clinic in New York City. He is assisted by super-capable Margaret Wyborn and less-than-capable Linda, who's only kept on because no one else can stand the doctor. Becker's best (some would say only) friend is the blind Jake Malinak, who runs a newsstand in the diner across the street. The diner used to be run by Reggie Kostas, but it has been taken over by Chris Conner, a lady whom Becker fluctuates between loathing and being attracted to. The diner is also frequented by Robert Benito, who is universally known as Bob and is the super at Becker's apartment (much to the doctor's regret).

The stable wormhole discovered by the Deep Space Nine crew is known to the Bajoran people as the Celestial Temple of their Prophets. Sisko, as discoverer of the wormhole and its inhabitants, is therefore the Emissary of Bajoran prophesy. The wormhole's other end is in the Gamma Quadrant, halfway around the galaxy from Bajor. That section of space is dominated by the malevolent Dominion. The Dominion is led by the Changelings, the race of shapeshifters to which Odo belongs. As of the beginning of the sixth season, Cardassia has joined the Dominion, and together they are waging war on the Federation and their Klingon allies. The war is quickly becoming the most costly war ever for the Federation, and the Deep Space Nine crew must fight to protect their way of life.