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Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth., Competing Interests: Rebecca RoylanceLeadership: Google healthHonoraria: Daiichi Sankyo Europe GmbH, Daiichi Sankyo/Astra Zeneca, Daiichi Sankyo/Astra ZenecaConsulting or Advisory Role: Lilly, Daiichi Sankyo Europe GmbH, IQVIA, Daiichi Sankyo/Astra ZenecaTravel, Accommodations, Expenses: Roche/Genentech, Daiichi Sankyo Europe GmbH, Daiichi Sankyo Europe GmbH, BMSNo other potential conflicts of interest were reported.