Whereas significant anti-tumor responses are observed in most BRAF-mutant melanoma patients exposed to MAPK-targeting agents， resistance almost invariably develops. Here， we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism， therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly， pharmacological SREBP-1 inhibition sensitizes BRAF-mutant therapy-resistant melanoma to BRAF inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together， these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies.