In the mid-24th century, the Tzenkethi fought a war with the United Federation of Planets. Among the starships involved was the USS Okinawa, under the command of Captain Leyton, who had fought against a number of Tzenkethi raiders. (DS9: "The Adversary", "Paradise Lost")
In late 2371, a Founder posing as Federation Ambassador Krajensky informed Captain Benjamin Sisko that the current Autarch had been deposed. He ordered the USS Defiant to the Federation-Tzenkethi border to reinforce the Federation presence to the new leading faction. However, the entire mission had actually been engineered by the Dominion in an attempt to incite another war between the two powers; there never was a coup d'etat. After his identity was exposed, the Changeling commandeered the Defiant and attempted to attack a Tzenkethi settlement on M'kemas III, though he was stopped before the Defiant reached the planet. (DS9: "The Adversary")
This species was only mentioned in dialogue. The pronunciation of their species' name was "TSEN-keth-i" ("ts" as in "tsar"). 
Robert Hewitt Wolfe said, in December 2006, that he thought he had named the Tzenkethi by combining the name Kzinti (from Larry Niven's race of aliens that appeared in the Star Trek: The Animated Series episode "The Slaver Weapon") with Tsankth, after a race from the RuneQuest and HeroQuest RPGs. Wolfe also said he did not picture them as cats like the Kzinti, but as being like the Hakazit from Jack L. Chalker's Well of Souls novels. He saw the Tzenkethi as being "heavily-armored lizard things." 
According to Star Trek: Star Charts (p. 36), the Tzenkethi government was named the Tzenkethi Coalition. The capital of the Coalition was located in the Tzenketh planetary system. This system consisted of a primary and at least one planet. The primary was named Tzenketh. This was a Class M star with a magnitude of +9.
Tzenkethi were also referred to in the novel Articles of the Federation. They join the Typhon Pact (β), an alliance of non-Federation powers, in the novel A Singular Destiny. Several Tzenkethi characters appear in the Star Trek: Typhon Pact novel Rough Beasts of Empire. In these novels, they are described as being humanoid in shape, and extremely attractive to many different races. Because of their internal biology which is effectively various fluid-filled sacs, they have a very fluid movement. Their skin pigmentation apparently ranges across the entire visible spectrum, in addition to having a slight phosphorescent glow. Bioluminescence is also common on the Tzenkethi homeworld. The later Typhon Pact novels Plagues of Night, Raise the Dawn, Brinkmanship, the eBook The Struggle Within, and the DS9 novels The Missing and Sacraments of Fire also feature Tzenkethi characters.
The Tzenkethi are mentioned in the Star Trek Online mission "Echoes of Light," designed by concept artist Hector Ortiz, based on Wolfe's initial description: contrary to their appearance in the novels above, they are depicted as hulking humanoids of an almost draconic appearance, with raspy voices and four arms. While investigating the seemingly barren planet of Draconis III, the Lukari captain Kuumaarke realizes that a protomatter bomb was set off here and it was of Tzenkethi design. When this is told to Admiral Jorel Quinn, he admits displeasure at this and is seeking both diplomatic and military solutions.  The Tzenkethi become the primary antagonists of the "New Frontiers" story arc, starting with the mission "Of Signs and Portents", where they are detonating protomatter bombs on numerous inhabited planets in the Alpha Quadrant, and it is eventually revealed in a later mission, "Melting Pot", that they are trying to combat a race called the Drantzuli. "Scylla and Charybdis" reveals that the Drantzuli are a caretaker race who have brought back the Hur'q. Tzenkethi Admiral Aarn Tzen-Tarrak initially claims to have refused to talk to the Federation, Klingon Empire, or Romulan Republic because of their stances - the Federation would have been too unwilling to risk other races, the Klingons would not have seen honor in what amounted to outright genocide, and they outright dismissed the "weak" Romulans. However, the subsequent "Gamma Quadrant" story arc ultimately reveals the Female Changeling had been impersonating Tzen-Tarrak the entire time in an attempt to use the Tzenkethi to exterminate the Hur'q, which the Dominion had created in the first place. A dialog in "Storm Clouds Gather" also states the Tzenkethi fell into a civil war as a result of the failed campaign.