A historical to present-day account of efforts to answer the question: “What puts the brakes on mammalian hair cell regeneration?”

Hearing and balance deficits often affect humans and other mammals permanently, because their ears stop producing hair cells within a few days after birth. But production occurs throughout life in the ears of sharks, bony fish, amphibians, reptiles, and birds allowing them to replace lost hair cells and quickly recover after temporarily experiencing the kinds of sensory deficits that are irreversible for mammals. Since the mid 1970s, researchers have been asking what puts the brakes on hair cell regeneration in mammals. Here we evaluate the headway that has been made and assess current evidence for alternative mechanistic hypotheses that have been proposed to account for the limits to hair cell regeneration in mammals.

► A past to present-day review of studies on hair cell regeneration is presented.
► Early work showed that supporting cells give rise to new hair cells in non-mammals, but the question remains whether mammalian ears may harbor reserve stem cells.
► Hypotheses for mechanisms that limit hair cell regeneration in mammals are proposed.