BACKGROUND AND OBJECTIVES: Breast cancer is the most common malignant neoplasm worldwide and the most prevalent one among women. It represents the leading cause of cancer-related death among females. Cyclin-dependent kinase 4 and 6 inhibitors disrupt the cell cycle, inducing cellular senescence and, ultimately, apoptosis. Consequently, they have become a novel type of adjuvant therapy for the treatment of advanced or metastatic breast cancer characterised by positive hormone receptors and human epidermal growth factor receptor 2 (HER-2) negative. METHODS: A systematic review was conducted, analysing the available literature on cyclin-dependent kinase 4 and 6 inhibitors published over the last five years. The aim was to evaluate the efficacy and safety of adding these drugs to the standard endocrine therapy for this pathology. RESULTS: The combination of cyclin-dependent kinase 4 and 6 inhibitors with endocrine therapy was shown to improve progression-free survival, overall survival, and chemotherapy-free intervals in patients who received this combination therapy. CONCLUSIONS: The addition of CDK4/6 inhibitors to endocrine therapy in the treatment of advanced or metastatic breast cancer with positive hormone receptors and HER-2 negative significantly improved PFS, median survival, and chemotherapy-free intervals compared with the use of hormonal treatments alone or in combination with a placebo. Currently, CDK4/6 inhibitors are becoming established as a new standard treatment for this pathology, offering lower toxicity than chemotherapy. However, it is necessary to deeply investigate the mechanisms of treatment resistance and develop effective therapies to overcome them.