Antissa claimed the inventor of the seven-stringed lyre. Terpander, born here in the seventh century BC, is credited with expanding the instrument from four strings to seven and shaping the foundations of Greek music. For a small Aeolian city on the edge of the Aegean, this was no small inheritance. The Greeks themselves were unsure where the name Antissa even came from. One tradition said it honored a daughter of Macar, the legendary king of Lesbos; another, his wife. A cleverer guess broke the word into ant' Issa, opposite Issa, claiming Antissa had once been an island facing a larger landmass then called Issa. The historian Myrsilus, writing in the third century BC, favored this version, and the city's low promontory jutting just offshore lent it some plausibility. Even the ancients, it seems, were guessing at their own origins.

Antissa had a habit of backing the wrong cause. In 428 BC it joined the revolt of Mytilene against Athens during the Peloponnesian War and fought off an attack by neighboring Methymna, only to be recovered by Athens once Mytilene fell. Decades later it sheltered the Athenian general Iphicrates when he fled a quarrel with his Thracian father-in-law. In the 330s a tyranny ruling Antissa and nearby Eresos was overthrown by the forces of Alexander the Great. The end came in 168 BC. When the Antissans gave harbor and supplies to Antenor, an admiral of Perseus, the last king of Macedonia, Rome punished the city for the choice. After Perseus fell, the Romans destroyed Antissa and moved its people to Methymna. The city that had survived Athens and Alexander did not survive Rome.

The British archaeologist Winifred Lamb excavated Antissa for the British School at Athens, uncovering stretches of the city wall and Iron Age buildings, among them an apsidal structure from the deep past. The original island site is now tied to the mainland by a sandy isthmus, the sea having slowly stitched it to the shore, and its most conspicuous remains are not ancient at all but those of a medieval castle. Traces of the old harbor mole still run along the eastern side. A village called Antissa carries the name today, with the cave of Orpheus nearby, and an older alternate name, Telonia, meaning sprite. The nightingales Myrsilus heard may be long gone, but the western end of Lesbos keeps its strange, half-mythical quiet, where the line between recorded history and Orpheus's drifting song was never quite firm.