Melanoma is a highly aggressive cancer with an alarmingly increasing incidence. A major question in melanoma biology is why are red-haired individuals at a high risk of developing melanoma. Polymorphisms in the melanocortin-1-receptor (MC1R) gene, encoding a trimeric G proteincoupled receptor activated by a-melanocyte-stimulating hormone (a-MSH), are frequently associated with red or blonde hair, fair skin, freckling and skin sensitivity to ultraviolet (UV) light, and several (RHC-polymorphisms) also associate with increased melanoma risk. However, some polymorphisms appear to affect melanoma risk independent of phenotype; using an in vivo model system we recently reported that some MC1R mutations synergize with UV to induce melanoma independently of their effects on melanogenesis. Understanding precisely how MC1R polymorphisms differentially affect melanoma biology is therefore a key issue. Importantly, we also found that UV irradiation triggered MC1R-interaction with and degradation of PTEN, leading to increased PI3K-signallingedriven senescence in melanocytes, but senescence bypass in BRaf mutant melanoma. Importantly, WT MC1R but not red-hair associated MC1R mutants could interact with PTEN. Furthermore, we used newly generated MC1R conditional RHC-polymorphism mouse models to dissect the tumor suppressive functions of MC1R in melanoma initiation in vivo and specifically its role in controlling PI3K signaling via PTEN degradation. Our studies identify intracellular molecular targets of MC1R in suppressing melanoma initiation that are directed towards identifying novel strategies for melanoma prevention and therapeutic intervention.