ABSTRACT The selector homeoproteins are a highly conserved group of transcription factors found throughout the Eumetazoa. Previously, the Drosophila selector homeoproteins Eve and Ftz were shown to bind with similar specificities to all genes tested, including four genes chosen because they were thought to be unlikely targets of Eve and Ftz. Here, we demonstrate that the expression of these four unexpected targets is controlled by Eve and probably by the other selector homeoproteins as well. A correlation is observed between the level of DNA binding and the degree to which gene expression is regulated by Eve. Suspecting that the selector homeoproteins may affect many more genes than previously thought, we have characterized the expression of randomly selected genes at different stages of embryogenesis. At cellular blastoderm, 25-50% of genes whose transcription can be monitored are regulated by both Eve and Ftz. In late embryogenesis, 87% of genes are directly or indirectly controlled by most or all selector homeoproteins. We argue that this broad control of gene expression is essential to coordinate morphogenesis. Our results raise the possibility that each selector homeoprotein may directly regulate the expression of most genes.