Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to transformation of melanocytes indicating that CDK4 can act as an oncogene in melanoma. To explore if CDK4 may be a viable target for the treatment of human melanoma we screened a panel of melanoma cells with a highly selective CDK4/6 inhibitor PD-0332991 (PD-991). To explore possible genomic predictors of sensitivity we also performed gene expression profiling and mutation analysis on these cells. CDK4 is highly expressed in melanoma cell lines compared to CDK6. The majority of melanoma cells were sensitive to PD-991, however there was a distinct resistant group. Low CDKN2A mRNA expression or mutation or loss of CDKN2A predicted sensitivity to PD-991 with 16 out of 19 mutant/loss cell lines being sensitive compared to only 2/6 wild type lines (p<0.03). In addition, mutated p53 and low MDM2 and p21 gene expression (p53 transcriptional activity) was a strong predictor of PD-991 resistance (p<0.0001). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to PD-991. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic predictor of sensitivity whereas p53 mutation a marker of resistance.