NRAS-mutant melanomas are extremely aggressive and highly resistant to currently available therapeutic modalities. Hence, new targets and therapeutic strategies for NRAS-driven melanomas are needed. As blocking NRAS directly has not been possible thus far, targeting downstream NRAS effectors, such as MAPK/ERK kinase (MEK), is being evaluated as an alternative therapeutic approach. However, blocking this pathway alone has limited efficacy. In this issue, Posch et al. report on a combination approach co-targeting polo-like kinase 1 and MEK in NRAS-mutant melanomas. This combination triggers a dual blockade of the cell cycle machinery, leading to apoptosis, and providing a new strategy to treat NRAS-mutant melanoma.