The harnessing in clinical practice of cyclin-dependent kinases 4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, has substantially changed the therapeutic approach for hormone receptor-positive metastatic breast cancer (BC). Phase II–III clinical trials evaluating the addition of these agents to standard endocrine therapy reported consistent improvements in response rates and progression-free survival as well as manageable toxicity profiles and excellent impact on patients’ quality of life. Hence, pivotal trials provided comparable results among different cyclin-dependent kinases 4/6 inhibitors, there is an increasing interest in finding substantial differences in order to implement their use in clinical practice. The aim of this paper is to summarize the current evidences raised from preclinical and clinical studies on cyclin-dependent kinases 4/6 inhibitors in BC, focusing on differences in terms of pharmacological properties, toxicity profile, and patients’ quality of life.