The cyclin-dependent kinases 4 and 6 inhibitors are the mainstay of treatment for patients with hormone receptor-positive and HER2-negative breast cancer. The ability of these drugs to improve the outcome of patients both in the metastatic and the early setting has been largely demonstrated. However, resistance, either de novo or acquired, represents a major clinical challenge. In the past years, efforts have been made to identify biomarkers that might help in a better selection of patients or to unravel the mechanisms leading to resistance in order to develop new therapeutic strategies to overcome it. Alterations of cell cycle-related genes and proteins are among the best characterized markers of resistance, and pathways impacting the cell cycle, including nuclear and growth factor receptors signaling, have been thoroughly investigated. Despite this, to date, cyclin-dependent kinases 4 and 6 inhibitors are administered based only on the hormone receptor and HER2 status of the tumor, and patients progressing on therapy are managed with currently available treatments. Here we summarize present knowledge on the cyclin-dependent kinases 4 and 6 inhibitors’ mechanisms of action, efficacy data, and mechanisms of resistance.