Radiotherapy is an essential part of curative and palliative oncologic treatment protocols, used in more than 50% of all patients with a cancer diagnosis, including skin cancers. Radiation damages rapidly dividing tumor cells and has a killing effect not only on tumor cells, but also on normal tissue cells in the irradiation field. Despite the increasing accuracy of radiotherapy, normal tissues are still unavoidably exposed, and damage to healthy tissue in the radiation field surrounding the area of malignancy remains a serious collateral effect. Skin has a high cellular proliferation rate, for this reason it is particularly radiosensitive. Stem cells are considered the major target of ionizing radiation and the cell response to radiation seems to vary as a function of keratinocyte degree of immaturity and quiescence. Irradiation activates signaling pathways which lead to the expression and activation of proinflammatory, profibrotic cytokines, coagulation cascade, and vascular injury. Cell death leads to chronic oxidative stress; inflammatory response and oxidative stress interact and promote each other. Radiation fibrosis is a complex process attributed to the imbalance of proinflammatory and profibrotic cytokines and TGF-β acts as the master fibrosis driver. Skin damage is impacted by patient age, physical condition, skin type, site, extension, dose, and duration of radiation exposure. Non-melanoma skin cancers have different radiosensitivity based on histological type and take advantage of alternative fractionations.