There has been great interest in developing in vitro tests as predictors of phototoxicity, which may be manifested in vivo in both animals and humans with symptoms ranging from erythema to blistered, raw skin following exposure to ultraviolet light (UVR), including sunlight, after topical or systemic administration of certain drugs. Photogenotoxicity is of interest due to the fact that some phototoxic drug classes have been demonstrated to be co-carcinogens with UVR in a hairless mouse model, specifically psoralens, retinoids, and fluoroquinolones. Treatment with 8-methoxy-psoralen and UVA has been shown to be carcinogenic in humans as well. Both microorganisms and mammalian cells have been used to develop in vitro assays for phototoxicity or photogenotoxicity. Many of the in vitro photogenotoxicity tests are standard genotoxicity assays with a UVR exposure component. Although some of these assays have been used as screens, they have not replaced the in vivo tests done in rodents. More data will be required from both in vitro and in vivo models before the in vitro assays can be accepted as surrogates for in vivo assays and the actual risk to humans can be better extrapolated as the relationships between phototoxicity, photogenotoxicity and photocarcinogenicity are elucidated.