Decoding the cis-regulatory logic of eukaryotic genomes requires knowledge of the DNA-binding specificities of all transcription factors. New work (Berger et al., 2008; Noyes et al., 2008) provides individual specificities for nearly all Drosophila and mouse homeodomains, key DNA-binding domains in many transcription factors. The data underscore the complexity of determining target specificities in vivo.