In recent years, the advent of CDK4/6 inhibitors has markedly transformed the therapeutic landscape of hormone receptor (HR)-positive breast cancer. Currently, the combination of CDK4/6 inhibitors—such as palbociclib, ribociclib, abemaciclib, and dalpiciclib—with endocrine therapy represents a cornerstone strategy for the management of advanced HR-positive, HER2-negative disease. Clinical trials have consistently demonstrated significant improvements in progression-free survival (PFS), with emerging evidence suggesting potential overall survival (OS) benefits. Although these agents are generally well-tolerated, adverse events such as neutropenia require vigilant clinical monitoring. Future research efforts are warranted to optimize individualized dosing strategies and refine toxicity management. This expert review synthesizes current clinical evidence on the efficacy and safety of CDK4/6 inhibitors, providing clinicians with an updated perspective to inform therapeutic decision-making