Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food–effect and drug–drug interaction studies, and highlight exposure–response and exposure–toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40–95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure–efficacy relationship has been described, while for palbociclib and ribociclib exposure–response analyses remain inconclusive. Future studies are needed to address exposure–efficacy relationships to further improve dosing.