Exposure to environmental factors and genetic predisposition of an individual may lead individually or in combination to various genetic diseases including cancer. These diseases may be a consequence of genetic instability resulting in large-scale genomic rearrangements, such as DNA deletions, duplications, and translocations. This review focuses on mouse assays detecting genetic instability at endogenous loci. The frequency of DNA deletions by homologous recombination at the pink-eyed unstable (p(un)) locus is elevated in mice with mutations in ATM, Trp53, Gadd45, and WRN genes and after exposure to carcinogens. Other quantitative in vivo assays detecting loss of heterozygosity events, such as the mammalian spot assay, Dlb-1 mouse and Aprt mouse assays, are also reviewed. These in vivo test systems may predict hazardous effects of an environmental agent and/or genetic predisposition to cancer.