Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer represents the most prevalent subtype, with endocrine therapy (ET) serving as the primary treatment approach. While anti-estrogen therapies are initially effective in most patients, around 50% of HR+ cases eventually develop resistance to ET, resulting in disease recurrence and limited long-term benefit. The introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors—palbociclib, ribociclib, and abemaciclib—combined with ET has significantly improved outcomes in HR+ advanced breast cancer (ABC) by targeting cell-cycle regulation and mitigating certain mechanisms of endocrine resistance. Nonetheless, identifying which patients are most likely to benefit, defining the key characteristics for optimal patient selection, and discovering predictive biomarkers of response remain unresolved. This review discusses the mechanisms of action of CDK4/6 inhibitors, potential resistance pathways, their clinical implications, and emerging strategies aimed at enhancing their effectiveness to improve survival and quality of life in patients with HR+, HER2− ABC.
