Metastasis proceeds through multiple steps and restrictive bottlenecks. Factors including the germline, tumour cell of origin, cancer cell plasticity, host tissue stroma, and response to therapy may influence the emergence of metastatic traits, and the probability that a cancer cell will complete all the steps towards overt metastasis. The pre-colonization phase of metastasis involves a series of events that cancer cells go through in a time scale of minutes to hours, including: (1) local invasion of cancer cells in the primary tumour, (2) intravasation into the tumour vasculature, (3) circulation of cancer cells as single cells or cell clusters, coated with platelets, (4) arrest in capillaries at the distant site and, (5) extravasation into the parenchyma of target organs for metastatic colonization. Colonization can be parsed into many steps that occur in a time scale of years. After extravasation, metastatic colonization comprises (6) resistance to immunity and other host tissue defences, (7) settlement in supportive niches for survival and retention of stem-like tumour-initiating capacity, (8) entry into latency as single cells, or (9) as indolent micrometastases. During the latency phase, which can last from months to decades, disseminated cancer cells must achieve long-term survival and may acquire traits for the eventually overtaking of the host tissue. The disseminated cancer cells may then break out of latency, reinitiating overt outgrowth (10), and overtaking the local tissue microenvironment (11). Once metastases become clinically manifest, therapeutic treatment may partially eliminate the tumour (12). However, under therapy-induced stress, cancer cells and non-neoplastic stromal cells mobilize survival signals (13) that nurse the residual disease until minority drug-resistant clones emerge and lead the outgrowth of a drug-resistant tumour (14). Different host tissue microenvironments select for cancer cells with distinct metastatic traits, giving rise to organ-specific metastatic cell populations.