Like other members of the Polycomb group, the extra sex combs gene (esc) is required for the correct repression of loci in the major homeotic gene complexes. We show here that embryos lacking both maternal and zygotic esc+ function display transient, general derepression of both the Ultrabithorax (Ubx) and Antennapedia (Antp) genes during germ band shortening, but Sex combs reduced (Scr) expression is almost normal in the epidermis and lacking in the central nervous system (CNS). In addition, embryos that are maternally esc- but receive two paternal copies of esc+ often are characterized by ectopic expression of the three homeotic genes, especially Ubx and Antp in the CNS. Imaginal discs from these paternally rescued embryos may show discrete patches of expression of Ubx and Scr in inappropriate locations. Thus, lack of esc+ function during a brief period in early embryogenesis results in a heritable change in determined state, even in a genetically wild type animal. Within these ectopic patches, homeotic gene expression may be regulated by the disc positional fields and by cross-regulatory interactions between homeotic genes.