The Drosophila dRYBP gene has been described to function as a Polycomb-dependent transcriptional repressor. To determine the in vivo function of the dRYBP gene, we have generated mutations and analyzed the associated phenotypes. Homozygous null mutants die progressively throughout development and present phenotypes variable both in their penetrance and in their expressivity, including disrupted oogenesis, a disorganized pattern of the syncytial nuclear divisions, defects in pattern formation, and decreased wing size. Although dRYBP mutations do not show the homeotic-like phenotypes typical of mutations in the PcG and trxG genes, they enhance the phenotypes of mutations of either the Sex comb extra gene (PcG) or the trithorax gene (trxG). Finally, the dRYBP protein interacts physically with the Sex comb extra and the Pleiohomeotic proteins, and the homeotic-like phenotypes produced by the high levels of the dRYBP protein are mediated through its C-terminal domain. Our results indicate that the dRYBP gene functions in the control of cell identity together with the PcG/trxG proteins. Furthermore, they also indicate that dRYBP participates in the control of cell proliferation and cell differentiation and we propose that its functional requirement may well depend on the robustness of the animal.