BACKGROUND Considerable controversy exists about the safety and efficacy of second re-irradiations (three courses of radiotherapy to overlapping volumes). Therefore, all published clinical studies were reviewed. MATERIAL AND METHODS Contemporary and historical articles were identified. Outcomes such as survival, local control, symptom improvement and side effects were extracted. Contemporary results were grouped by anatomical location of the re-irradiated region in the body. RESULTS Most data were derived from central nervous system tumors, pelvic tumors and bone metastases. We could include nine contemporary, retrospective studies with 2-25 patients each. Nearly, all patients were treated with palliative intent. Most of the prescribed re-irradiation regimens were highly individualized and thus difficult to compare. Symptomatic responses were recorded in most patients. In palliatively treated patients with pelvic and bony target volumes, high-grade toxicity was uncommon. CONCLUSIONS Despite of issues related to study size, length of follow-up and calculation of lifetime cumulative equivalent dose, the available data provide an initial framework for future studies and discussion of dose constraints. Selected dose-fractionation regimens may result in a satisfactory therapeutic ratio even after two previous courses of radiotherapy, if these were well tolerated.