Metastasis formation is an essential aspect of cancer, for which the molecular underpinning has long been subject to debate. Although the organ preference for dissemination is governed by tumor-host interactions on the epigenetic level there is a genetic basis to the ability of cancer cells to disseminate. Metastasis genes encode homing receptors, their ligands, and extracellular matrix-degrading proteinases, which jointly cause invasion and anchorage-independence. They are developmentally non-essential stress response genes that physiologically mediate the homing of immune system cells. Metastatic potential is conferred to cancer cells by aberrant expression or splicing of these genes. Oncogenes act upstream of metastasis genes. In cancer cells, oncogenic signaling activates distinct genetic programs leading to cell cycle progression and invasiveness, respectively. The expression of metastasis genes is regulated by multi-subunit transcription factor complexes. The identification of genes that direct cancer metastasis implicates them as candidate drug targets.