In vivo, UV radiation induces a series of morphological and ultrastructural alterations in human epidermis. These and other changes eventually lead to well described pathological modifications including erythema and cancer. Morphological alterations are easier to detect in cultured cells, such as human keratinocytes or other epithelial cells. One can use different intensities of different radiation types (UV-A, -B and -C) and expose cell monolayers to different doses. In these experimental conditions it is possible to evaluate radiation risks and to provide additional information thanks to the reproducibility and the enormous amplification of the phenomena normally occurring in vivo. Alterations observed in structural studies can be summarized as the succession of the following events: (i) cell retraction with loss of cell-cell interactions; (ii) surface blebbing; and eventually (iii) cell death. Cytoskeletal components play a key role in this cascade. Morphogenesis of these changes can be ascribed to oxidative modifications due to reactive oxygen species formation following radiation that can modify both cell membrane and cytoskeleton. The use of in vitro systems can be of great relevance in the understanding of the pathogenetic mechanisms of UV radiation changes and to determine possible drugs capable of counteracting UV-mediated subcellular pathology.