The transcription factors encoded by homeotic genes determine cell fates during development. Each homeotic protein causes cells to follow a distinct pathway, presumably by differentially regulating downstream ‘target’ genes. The homeodomain, the DNA-binding part of homeotic proteins, is necessary for conferring the specificity of each homeotic protein's action. The two Drosophila homeotic proteins encoded by Antennapedia and Sex combs reduced determine cell fates in the epidermis and internal tissues of the posterior head and thorax. Genes encoding chimeric Antp/Scr proteins were introduced into flies and their effects on morphology and target gene regulation observed. We find that the N terminus of the homeodomain is critical for determining the specific effects of these homeotic proteins in vivo, but other parts of the proteins have some influence as well. The N-terminal part of the homeodomain has been observed, in crystal structures and in NMR studies in solution, to contact the minor groove of the DNA. The different effects of Antennapedia and Sex combs reduced proteins in vivo may depend on differences in DNA binding, protein-protein interactions, or both.