Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK-inhibitor therapy may be considered in patients with NRAS-mutated melanoma that have failed all standard therapies. KEY POINTS: Melanomas harbor NRAS mutations in 10%-30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug-resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.