For successful infection, avian sarcoma leukosis virus subgroup A (ASLV-A) requires its receptor, tumor virus A (TVA), to be present on the surface of target cells. This is the basis of the RCAS-TVA gene delivery system: Mammalian cells lack the gene encoding TVA and are normally resistant to infection by ASLV; however, transgenic targeting of TVA to specific cell types or tissues in the mouse renders these cells uniquely susceptible to infection by ASLV-A-based RCAS viruses. The RCAS-TVA system is a powerful tool for effectively modeling human tumors, including pancreatic, ovarian, and breast cancers, gliomas, and melanomas. RCAS viruses can deliver cDNAs (≤ 2.8 kb), as well as short hairpin RNAs (shRNAs), microRNAs (miRNAs), and other noncoding RNAs. Compared with traditional transgenic and knockout mice, the RCAS-TVA system has several strengths. First, virus delivery is generally performed postnatally and results in a relatively low infection rate of target cells; the sporadic postnatal expression of the gene of interest mimics the situation in developing human tumors. Second, a single transgenic mouse line can be used to compare the consequences of specific genes on tumor development, with viruses encoding oncogenes or shRNAs targeting specific tumor suppressor genes. TVA mouse strains can also be easily combined with transgenic, knock-in, and knockout mouse models to study cooperating genetic events.