The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become the standard of care, in combination with antiestrogen therapy, for patients with hormone receptor–positive (HR+)/HER2− advanced breast cancer. Various preclinical and translational research efforts have begun to shed light on the genomic and molecular landscape of resistance to these agents. Drivers of resistance to CDK4/6i therapy can be broadly subdivided into alterations impacting cell-cycle mediators and activation of oncogenic signal transduction pathways. The resistance drivers with the best translational evidence supporting their putative role have been identified via next-generation sequencing of resistant tumor biopsies in the clinic and validated in laboratory models of HR+ breast cancer. Despite the diverse landscape of resistance, several common, therapeutically actionable resistance nodes have been identified, including the mitotic spindle regulator Aurora Kinase A, as well as the AKT and MAPK signaling pathways. Based upon these insights, precision-guided therapeutic strategies are under active clinical development. This review will highlight the emerging evidence, in the clinic and in the laboratory, implicating this diverse spectrum of molecular resistance drivers.