Metastasis remains the leading cause of cancer-associated mortality, and a detailed understanding of the metastatic process could suggest new therapeutic avenues. However, how metastatic phenotypes arise at the genomic level has remained a major open question in cancer biology. Comparative genetic studies of primary and metastatic cancers have revealed a complex picture of metastatic evolution with diverse temporal patterns and trajectories to dissemination. Whole-genome amplification is associated with metastatic cancer clones, but no metastasis-exclusive driver mutations have emerged. Instead, genetically activated oncogenic pathways that drive tumour initiation and early progression acquire metastatic traits by co-opting physiological programmes from stem cell, developmental and regenerative pathways. The functional consequences of oncogenic driver mutations therefore change via epigenetic mechanisms to promote metastasis. Increasing evidence is starting to uncover the molecular mechanisms that determine how specific oncogenic drivers interact with various physiological programmes, and what triggers their activation in support of metastasis. Detailed insight into the mechanisms that control metastasis is likely to reveal novel opportunities for intervention at different stages of metastatic progression.