In this study, we demonstrated that (i) cannabinoids have toxic, anti-tumour effects in multiple melanoma cell lines, although to a different extent, (ii) that cannabinoids mediate their effects via CB1R, TRPV1 and PPARα leading to mitochondrial, caspase-mediated cell death and (iii) that cannabinoids have no antagonistic effect when combined with modern targeted therapy in vivo. This evidence concerns the gene PPARA and melanoma.