Melanoma is the deadliest type of cancer that affects the largest organ of our body, the skin. In recent years, there is an increase in the incidence and aggressiveness of melanomas. The number of treatment options has grown considerably in the past few years, leading to significant improvements in both overall and progression-free survival. One of the attractive candidates in this wave of treatment options is a cell cycle controller: cyclin-dependent kinases (CDK) 4/6 inhibitors. CDK4/6, a class of serine/threonine kinases expressed in most cell types, controls the first gap phase (G1 to S) of the cell cycle, indicating its vital importance in both normal cellular processes as well as tumorigenesis. Up to 90% of melanoma patients have genomic mutations affecting various parts of CDK4/6 pathway. Noticeably, with the help of next-generation sequencing technology, mutations with high frequency in the CDK4 pathway were also identified in relatively rare subtypes of melanoma including acral melanoma and mucosal melanoma. Therefore, CDK4/6 inhibitors have emerged as powerful and promising anticancer therapies, especially in combination treatment with immunotherapies or other targeted therapies. In this review, we will provide an overview of current scientific knowledge regarding the oncogenic properties of CDK4/6 in melanomas, we mainly discuss the latest genomic and preclinical findings of CDK4 signaling in melanoma, the progress of CDK4 inhibition as combined with other therapies for overcoming resistance and summarize recent advances from clinical trials as well as ongoing studies which gives us a better scope into the effectiveness of CDK4/6 therapy in treating malignant melanomas. © 2020 Elsevier Masson SAS