Oncogenic transformation of normal cells and the establishment of transformed cells to form malignant tumors is a complex, multistep process influenced by viruses in multiple ways. The relationship between viruses and the immune system manifests itself, in part, through various roles of viruses in transformation of host cells, including cells of the immune system. A large number of viruses participate in oncogenic transformation of cells in many animal species. Candidates for oncogenic transformation in man are human T lymphotropic viruses I and II, certain human papillomavirus types, hepatitis B virus, and Epstein-Barr virus. Various mechanisms, which may overlap with one another, have been proposed to account for viral oncogenesis. These include introduction of a directly transforming viral gene, retroviral transduction of protooncogenes, mutagenesis, uncoupling of cellular protooncogene expression from normal regulatory controls, overexpression of normal cellular genes resulting from effects of viral cis- or trans-acting factors, and inactivation of tumor suppressor genes. A second critical area of interaction between viruses and the immune system is in the selection of transformed cells. When cell transformation is accompanied by expression of tumor antigens, the immune system may influence tumor cell establishment and selection of transformed cells for metastatic outgrowth. Finally, host well-being may be severely compromised when viruses infect cells of the immune system, leading to an inability to mount immunological responses specific for opportunistic microorganisms and for cells transformed by viruses or nonviral agents. Human immunodeficiency virus infection exemplifies this phenomenon, although other viruses also negatively affect the immune system. The role of normal immune responses in limiting tumor cell growth is evident from the increased incidence of malignancies in immunocompromised hosts.