The replicative pathways, modes of transmission, and pathobiology of retroviruses depend upon an interplay between mechanisms that control host gene expression and the expression of virus gene products. The nonacute transforming viruses that contain only the gag, pol, and env genes are dependent upon host gene trans-acting transcription factors for replication and expression. The host cell trans-acting factors vary according to cell type. For this reason, the tissue tropism and pathogenesis of these viruses depend upon the compatibility of cis-acting viral regulatory elements with the host trans-acting factors. Such interactions play a dominant role in determining tissue-specific tumor induction of murine retroviruses. Recently a group of retroviruses that induce trans-acting regulatory factors has been identified. The group includes etiologic agents of ATLL and AIDS. Compatibility between the virally encoded trans-acting gene regulatory factors and cis-acting regulatory elements of differentiated cells may play the dominant role in determining the tissue specificity and pathogenic effect of these viruses.