Palbociclib, a CDK4 inhibitor, in combination with standard breast cancer therapies, either letrozole or fulvestrant, is an approved treatment for ER-positive, HER2-negative advanced breast cancer, and is currently in clinical trials in combination with BRAF and MEK inhibitors for the treatment of metastatic melanoma. As with most targeted therapies, resistance to palbociclib develops, and in breast cancer and acute myelogenous leukemia it is due to either loss of RB or activation of CDK2 (Dean et al., 2010; Herrera-Abreu et al., 2016; Wang et al., 2007). In order to identify the mechanisms of resistance to palbociclib in melanoma, we developed models of resistant melanoma cell by subjecting the cells to constant drug pressure. In all palbociclib-resistant cell lines, irrespective of BRAF or NRAS status, CDK2 was identified as a driver of resistance via its ability to phosphorylate RB upon CDK4 inhibition, and was activated via multiple mechanisms. High throughput drug screening showed that in several palbociclib-resistant cell lines there was heightened sensitivity to protein arginine methyltransferase 5 (PRMT5) inhibitors. Analysis of protein and protein interactions revealed that PRMT5 is hyper-activated in palbociclib-resistant melanoma cells and mediated resistance via modulating CDK2 pathway. Inhibition of PRMT5 can inhibit the CDK2 pathway by altering levels of p21, a CDK2 inhibitor, or Cyclin E, a CDK2 activator. Combining palbociclib with GSK3326595, a PRMT5 inhibitor, restored sensitivity to palbociclib and potently prevented cell proliferation. In vivo, the combinatoin resulted in robust tumour growth inhibition and in delaying the emergence of resistance to palbociclib. Given that both CDK4 pathway and PRMT5 are deregulated in melanoma and other cancer, this combiantion can be a promising therapeutic approach and provide more treatment options for patients.