It has long been known that tumors become more clinically and biologically aggressive over time. This has been termed 'tumor progression' and includes, among other properties invasion and metastasis, as well as more efficient escape from host immune regulation. Since 1960, first cytogenetics and then molecular techniques have shown that tumors expand as a clone from a single altered cell, and that clinical 'progression' is the result of sequential somatic genetic changes, generating increasingly aggressive subpopulations within the expanding clone. Multiple types of genes have been identified, and they differ in different tumors, but they provide potential specific targets for important new therapies.