The skin tissue has the largest area in the human body and functions as both a barrier and a defender. As such, it tends to be the first tissue to be damaged. Advances in medical technology provide prospects as well as side effects, for example, radiation therapy for cancer. With increasing cancer morbidity and radiation widely applied for cancer therapy, radiation-induced skin injury (RSI) has become a serious concern. In recent decades, research efforts have focused on the mechanisms underlying RSI. This review summarizes the mainstream opinions on these mechanisms, including the pathological, molecular biological, and cytobiological alterations. Radiation-induced reactive oxygen species (ROS), cytokines and involved signaling pathways are evaluated. Other relevant aspects include radiation-induced skin fibrosis (RSF) and radiation-related skin cell senescence. Moreover, we review strategies for the prevention and treatment in clinical and pre-clinical studies to support the treatment of RSI during radiotherapy. The prevention strategies include dose control, pre-irradiation instructions, and RSI assessments, while the main treatments include physical therapy, external-use dressings or creams, biological therapy and surgical reconstruction.