Protein-DNA interactions control many aspects of animal development and cellular responses to the environment. Although profiling of individual transcription factor binding sites is not a reliable guide for predicting the position of cis-regulatory elements in large genomes, modelling the evolution and the organization of regulatory elements has provided enough information to make some successful predictions. For vertebrate genomes, the field is limited by the lack of sufficient experimental data upon which to build reliable models. Nonetheless, a combination of experimental, computational and comparative data is likely to reveal aspects of complex regulatory networks in vertebrates, just as it has already done for simple eukaryotic genomes.