Mensacarcin is a stereogenic complex polyketide with potent anti-tumor activity produced by a soil-dwelling Streptomyces bottropensis. The US National Cancer Institute (NCI) 60 human tumor cell line anticancer drug screen (NCI-60) reveals mensacarcin’s cytostatic properties in almost all tested cell lines and distinct cytotoxic properties specifically in eight melanoma cell lines with an average IC50 value of 0.5-1 μM. We show that mensacarcin activates caspase-3/7-dependent apoptotic pathways and induces apoptosis in melanoma cells and not colon cancer carcinoma cells. Mensacarcin co-localizes in mitochondria and impairs mitochondrial function by either inhibiting mitochondria respiration directly or by causing general mitochondrial dysfunction. Combination of mensacarcin and the standard chemotherapeutic regime for BRAF-mutant melanoma, vemurafenib/zelboraf®, increases efficacy and cytotoxicity synergistically.