The introduction of small molecule BRAF^V600 kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression-free survival compared with conventional chemotherapy. Beside BRAF^V600 inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF^V600 inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF^V600 inhibitors, evoking concern in clinical practice. We review interactions of BRAF^V600 inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue.