Many naturally occurring C-type RNA viruses are of endogenous origin. The genetic information for synthesizing these RNA viruses is present in the DNA of normal mouse cells, probably as part of their chromosomal DNA. Some C-type viruses infect mouse cells (homotropic virus), while others infect certain tissue culture cells from other species but not mouse fibroblasts (xenotropic virus). All mouse strains studied appear to contain endogenous xenotropic viral genomes. However, based on the regularity with which homotropic virus is detected, inbred mice can be divided into high, low, and non-virus-yielding strains. Nucleic acid hybridization studies have shown that DNA from high virus strains contains several copies of the homotropic virus genome, while that from low virus strains contains fewer copies, and DNA from nonvirus strains lacks a significant portion of the homotropic virus genome. In vivo and in vitro genetic studies support the nucleic acid hybridization results. In addition, high virus mouse strains are more likely than low virus strains to release virus that will replicate efficiently in their own cells. Methods for the activation and detection of endogenous C-type virus in tissue culture are discussed.