Two of the most common DNA-binding motifs found in eukaryotic transcriptional regulatory proteins are the homeodomain and the C 2 H 2 zinc finger. In Drosophila, homeodomain and zinc-finger proteins have been implicated in a wide variety of developmental processes. Until now, no proteins have been described in which both these DNA-binding motifs are present. We report here the isolation of genes encoding two such Drosophila proteins from a cDNA expression library. The product of the zfh-1 gene (z inc-f inger h omeodomain protein 1) contains one homeodomain and nine C 2 H 2 zinc fingers. The product of the zfh-2 gene processes three homeodomains and sixteen C 2 H 2 zinc fingers. For zfh-1, antisera raised against nonoverlapping regions of the gene product all recognize a 145 kDa protein on protein immunoblots, suggesting that the different DNA-binding motifs are actually all present in the mature gene product. The novel arrangement of interspersed homeodomain and zinc-finger motifs in the primary sequences of the zfh-1 and zfh-2 gene products may signify an unusual mechanism of transcriptional regulation by these proteins.