The rate and mechanisms of evolution of transcription factor binding show striking differences across diverse metazoan phyla. This Review highlights insights gained from sequence-based comparisons of genomes and ChIP–seq studies analysing the evolution of transcription factor binding, as well as their conceptual contribution to models of regulatory evolution and gene expression control. Differences in transcription factor binding can contribute to organismal evolution by altering downstream gene expression programmes. Genome-wide studies in Drosophila melanogaster and mammals have revealed common quantitative and combinatorial properties of in vivo DNA binding, as well as marked differences in the rate and mechanisms of evolution of transcription factor binding in metazoans. Here, we review the recently discovered rapid 're-wiring' of in vivo transcription factor binding between related metazoan species and summarize general principles underlying the observed patterns of evolution. We then consider what might explain the differences in genome evolution between metazoan phyla and outline the conceptual and technological challenges facing this research field.