When early blastocysts are subjected to immunosurgery, the resulting inner cell masses (ICMs) regenerate trophoblast cells. In contrast, ICMs from later blastocysts produce endoderm cells. We have found that if embryos are treated with cycloheximide during the transition from the early to late blastocyst stages, subsequently isolated ICMs give rise to trophoblast-like giant cells. These cells do not, however, exhibit detectable levels of delta 5, 3 beta-hydroxysteroid dehydrogenase, an enzyme normally found in primary trophoblast cells. Neither Colcemid nor alpha-amanitin affects the conversion of the ICM program in the same way as cycloheximide, although alpha-amanitin added at later stages interferes with the formation of a cohesive endoderm layer around the isolated ICM. We propose that the reprogramming of ICM cells involves at least two events: one terminates the giant cell program and the other, occurring later in development, promotes endoderm formation.