In 2268, the Federation first officially encountered the Tholians. Myths and legends of the Tholians had been common throughout neighboring sectors, although the UFP had believed that they were simply a myth: the "Flying Dutchmen" of space. The U.S.S. Defiant found out differently when the Tholians trapped the starship in an interphasic field, the famous "Tholian web." The field disrupted the central nervous systems of the crew, causing mass insanity before it sublimated the Defiant into a pocket dimension only tangentially connected to "normal space." Investigating the disappearance of the Defiant, the U.S.S. Enterprise came "face to face" with the Tholians. Although briefly trapped in the Tholian interphase field, the Enterprise managed to escape before the Tholians could destroy it.

Tholians would not travel far from their borders but destroyed any trespassers into a Tholian "annex." UFP policy regarding the Tholians was to avoid contact and warn vessels against venturing into Tholian space. As relations improved between the Federation and the Klingon Empire, however, more ships traveled along the borders of Tholian space. Reports of space pirates, unexplained time-space phenomena, and the disappearance of several merchant vessels prompted Starfleet to send patrols to Tholian space once again. In 2351, Bolian Admiral Taneko saved a Starfleet task force when he detonated the warp core of the crippled U.S.S. Mizar to decimate an attacking Tholian fleet.

Starfleet constructed Starbase 277 on the Tholian border in 2352 to monitor Tholian activities and to coordinate escorts for civilian craft. At the time, the Tholians considered the base to be an intrusive and militant move by Starfleet. The starbase was attacked four days after it became fully operational in 235. All personnel aboard Starbase 277 were killed except for Kyle Riker, a civilian mathematician advising Starfleet on Tholian tactical matrices.

The U.S.S. Fearless led a task force which blunted the Tholian assault and began a blockade of the border sectors, hoping to outlast the Tholians with a purely defensive strategy of attrition. However, the Tholians are tireless in defending their territory. Andorian Admiral Temrev proposed a change of strategy, suggesting an invasion in force into the heart of the Tholian Assembly. By carrying the war to the intensely private Tholians, Temrev hoped to increase the incentives for peace. Starfleet approved Temrev's plan, and the U.S.S. Lor'vela led a squadron of starships into the Tholian core sectors while the Fearless maintained a defensive reserve. New Tholian technologies finally stalled the Lor'vela's offensive, but the attack had done its work.

In 2360, Betazoid diplomats arrived in Tholian space to negotiate a truce with the Tholians. Although many veterans of the war were skeptical that peace could ever come, the Betazoids succeeded. The Tholians were frustrated with the war and willing to listen to peace proposals. The Tholians and the Federation signed the Tholian Accords that year, which ended open conflict between the powers and restored the border to the status quo. For years, the Tholian border remained quiet, although formal diplomatic ties remained elusive. Finally, in 2369, the Tholians stunned the Federation by proposing normalized relations between the two powers. Later that same year, both sides agreed to an exchange of ambassadors and trade.