Although a minor element of modern marine fauna, Agnatha were prominent among the early fish in the early Paleozoic. Two types of Early Cambrian animal apparently having fins, vertebrate musculature, and gills are known from the early Cambrian Maotianshan shales of China: Haikouichthys and Myllokunmingia. They have been tentatively assigned to Agnatha by Janvier. A third possible agnathid from the same region is Haikouella. A possible agnathid that has not been formally described was reported by Simonetti from the Middle Cambrian Burgess Shale of British Columbia.

Many Ordovician, Silurian, and Devonian agnathans were armored with heavy bony plates. The first armored agnathans—the Ostracoderms, precursors to the bony fish and hence to the tetrapods (including human beings)—are known from the middle Ordovician, and by the Late Silurian the agnathans had reached the high point of their evolution. Agnathans declined in the Devonian and never recovered.