Tumorigenesis occurs when cells undergo a series of genetic and epigenetic events that upset the balance of cell death, proliferation and differentiation. In a few cases, alterations in key regulatory steps have been identified, facilitating the design of rational cancer therapies. However, the karyotypic complexity exhibited by most solid tumors makes it challenging to identify the lesions underlying specific tumor phenotypes in most cancers. Work from many laboratories indicates that the acquisition of the tumorigenic phenotype requires several cooperating events and that a finite set of genetic alterations suffices to transform cells derived from numerous different lineages. Experimental models derived from the manipulation of oncogenes, tumor suppressor genes and telomerase provide useful platforms to delineate pathways involved in cell transformation, to connect specific cancer-associated mutations with particular cancer phenotypes and to discover and validate new targets for therapeutic development. Here we review the development of such experimental models and recent work combining such model systems with increasingly powerful genetic and chemical tools to identify and validate genes involved in malignant transformation.