We have reported that 1-day-old post-hatch chick lens epithelial cells lose the capacity for lentoid body formation and δ-crystallin expression during long-term serial subculture, although they continue to synthesize, but not to accumulate, α- and β-crystallins, even in cells with a transformed phenotype. Here we present evidence that dedifferentiation may reflect an age-related change in the capacity for response to regulatory signals. We have tested the capacity of these cells in serial subcultures to respond to agencies which affect lens cell growth and differentiation in primary culture: retinoic acid (RA), insulin, cAMP and bovine retinal extract (BRE). Secondary cultures responded only to RA and BRE, by an increase in lentoid formation and by α- and β-accumulation, while RA also restored δ-crystallin expression. Later cultures showed no such responses. The results suggest that the process of lens cell dedifferentiation may, at first, be reversible but later becomes irreversible, despite the continuing persistence of low levels of crystallin expression. © 1990.