Interactions of cells with their microenvironment modify the cellular sensitivity of normal and tumor cells for radiation- and drug-induced genotoxic injury. The preexistent or acquired cellular resistance against such agents aggravates anticancer therapies and, therefore, complicates the recovery of patients. Recently, integrin-mediated adhesion was shown to improve cell survival of both normal and cancer cells following DNA damage. Here, I will discuss the role of integrins and integrin-mediated signaling cascades in the survival or death response upon genotoxic stress. Detailed knowledge of the responsible molecular processes might provide implications for putative therapies targeting integrins or integrin-associated molecules to achieve an optimization of anticancer treatments.