Instructions for when, where and to what level each gene should be expressed are encoded within regulatory sequences. The importance of motifs recognized by DNA-binding regulators has long been known, but their extensive characterization afforded by recent technologies only partly accounts for how regulatory instructions are encoded in the genome. Here, we review recent advances in our understanding of regulatory sequences that influence transcription and go beyond the description of motifs. We discuss how understanding different aspects of the sequence-encoded regulation can help to unravel the genotype–phenotype relationship, which would lead to a more accurate and mechanistic interpretation of personal genome sequences.