CDK4/6 inhibitors have become a cornerstone in the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer. These inhibitors, when combined with endocrine therapy (ET), significantly improve progression-free survival (PFS) and overall survival (OS) in patients. The FDA has approved several CDK4/6 inhibitors, including palbociclib, abemaciclib, and ribociclib, for first-line treatment in HR+/HER2- breast cancer. Clinical trials such as PALOMA-2, MONALEESA-2, and MONARCH-3 have demonstrated that CDK4/6i combined with ET provides substantial benefits, particularly in postmenopausal women. The combination of CDK4/6i with fulvestrant or aromatase inhibitors (AI) has shown comparable or superior outcomes in endocrine-sensitive populations. In endocrine-resistant populations, abemaciclib has shown significant benefits, while ribociclib and palbociclib have not. For patients with bone metastases, CDK4/6i have shown promise, particularly in those with bone-only disease. In visceral metastases, CDK4/6i combined with ET has improved PFS and OS. CDK4/6i also show potential in combination with HER2-targeted therapy, enhancing the effectiveness of treatment in HER2+ breast cancer. Additionally, CDK4/6i may enhance antitumor immune responses, although their combination with immune checkpoint inhibitors has not shown significant benefits. The mechanism of action of CDK4/6i involves inhibiting CDK4/6, leading to cell cycle arrest and reduced tumor growth. However, these inhibitors can cause adverse effects such as neutropenia, QT interval prolongation, and liver toxicity. The choice of CDK4/6i should be based on patient-specific factors, including metastatic sites, organ function, and prior treatment. Overall, CDK4/6i have revolutionized the treatment of HR+ breast cancer, offering more effective and personalized therapeutic options.CDK4/6 inhibitors have become a cornerstone in the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer. These inhibitors, when combined with endocrine therapy (ET), significantly improve progression-free survival (PFS) and overall survival (OS) in patients. The FDA has approved several CDK4/6 inhibitors, including palbociclib, abemaciclib, and ribociclib, for first-line treatment in HR+/HER2- breast cancer. Clinical trials such as PALOMA-2, MONALEESA-2, and MONARCH-3 have demonstrated that CDK4/6i combined with ET provides substantial benefits, particularly in postmenopausal women. The combination of CDK4/6i with fulvestrant or aromatase inhibitors (AI) has shown comparable or superior outcomes in endocrine-sensitive populations. In endocrine-resistant populations, abemaciclib has shown significant benefits, while ribociclib and palbociclib have not. For patients with bone metastases, CDK4/6i have shown promise, particularly in those with bone-only disease. In visceral metastases, CDK4/6i combined with ET has improved PFS and OS. CDK4/6i also show potential in combination with HER2-targeted therapy, enhancing the effectiveness of treatment in HER2+ breast cancer. Additionally, CDK4/6i may enhance antitumor immune responses, although their combination with immune checkpoint inhibitors has not shown significant benefits. The mechanism of action of CDK4/6i involves inhibiting CDK4/6, leading to cell cycle arrest and reduced tumor growth. However, these inhibitors can cause adverse effects such as neutropenia, QT interval prolongation, and liver toxicity. The choice of CDK4/6i should be based on patient-specific factors, including metastatic sites, organ function, and prior treatment. Overall, CDK4/6i have revolutionized the treatment of HR+ breast cancer, offering more effective and personalized therapeutic options.