In melanoma the development of resistance to BRAF inhibitors limits clinical responses. Thus the search for novel single agent and combination therapies as well as sequencing strategies that overcome or delay the emergence of resistance is needed. The p16-CDK4- cyclinD-RB1 pathway (CDK4 pathway) is deregulated in approximately 90% of melanomas and most melanoma cell lines are sensitive to palbociclib a specific CDK4/6 inhibitor. We hypothesized that dual targeting the MAPK/ERK and CDK4 pathways would lead to robust inhibition of the CDK4/Cyclin D complex and consequently induce greater tumour regression than single agent treatment. In vitro, melanoma cells treated with PLX4720, palbociclib or their combination inhibited cell proliferation and clonogenic survival, however, only the combination led to sustained inhibition. Furthermore, the response to either an intermittent or sequential dosing schedule was inferior to constant combination therapy. The combination induced rapid cell cycle arrest followed by either cell death or senescence. In A375 and HT144 human tumor xenograft models, initially tumour regression and tumour stasis was induced by palbociclib and PLX4720, respectively, but resistance eventually developed to both agents. In contrast, the combination treatment induced rapid and sustained tumour regression. Biomarker studies indicate resistance to single agent PLX4720 was due to reactivation MAPK/ERK pathway and resistance to palbociclib to partial restoration of phosphorylated RB1. Tumour regression in the combination treatment was associated with the infiltration of leukocytes including activated natural killer cells indicating that these cells were involved in tumour clearance. These data demonstrate that dual targeting CDK4/6 and mutant BRAF evades resistance to single agents and leads to sustained tumor regression