BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therapy for patients with NRASmutant melanoma is difficult. Our own studies showed that BRAF inhibitors amplify the effects of MEK inhibitors in NRASmutant melanoma. This study aimed at identifying a BRAF and MEK inhibitor combination with superior anti-tumor activity to the three currently approved combinations. We, thus, assessed anti-proliferative and pro-apoptotic activities of all nine as well as resistance-delaying capabilities of the three approved inhibitor combinations in a head-to-head comparison in vitro. The unconventional combination encorafenib/trametinib displayed the highest activity to suppress proliferation and induce apoptosis, acting in an additive manner in BRAFmutant and in a synergistic manner in NRASmutant melanoma cells. Correlating with current clinical studies of approved inhibitor combinations, encorafenib/binimetinib prolonged the time to resistance most efficiently in BRAFmutant cells. Conversely, NRASmutant cells needed the longest time to establish resistance when treated with dabrafenib/trametinib. Together, our data indicate that the most effective combination might not be currently used in clinical settings and could lead to improved overall responses.