Much of what we know about the chromatin-based mechanisms that regulate gene expression in mammals has come from the study of what are, paradoxically, atypical genes. These are clusters of structurally and/or functionally related genes that are coordinately regulated during development, or between different cell types. Can unravelling the mechanisms of gene regulation at these gene clusters help us to understand how other genes are controlled? Moreover, can it explain why there is clustering of apparently unrelated genes in mammalian genomes?