Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform "class effect." In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g.,