(McGinnis et al., 1984a, b; Scott & Wiener, 1984), this highly conserved DNA-binding domain has been found indozens of transcription factors (Scott et al., 1989; Rosenfeld, 1991). Genetic and molecular studies of Drosophila have identified more than 20 homeodomain proteins that regulate cell de-termination within specific developmental pathways (Akam, 1987; Hayashi & Scott, 1990). Vertebrate homologues have been identified for almost every known Drosophila homeo-domain, providing a starting point for directed mutational analysis of vertebrate development (Kessel & Gruss, 1990). The regulatory function of a homeodomain protein derives from the specificity of its interactions with DNA and pre-sumably with components of the basic transcriptional ma-chinery such as RNA polymerase or accessory transcription factors. Although little is known about thesecond type of specificity, the lastseveral years have witnessed important advances in our understanding of how homeodomains contact DNA. The most important contributions have been the de-termination of three-dimensional structures for two homeo-domain-DNA complexes (Otting et al., 1990; Kissinger et al.,