<p>Cyclin-dependent kinases (CDKs) are key regulators of cell-cycle progression and have long been recognized as attractive therapeutic targets in oncology. Inhibitors of CDK4 and CDK6 have transformed the treatment of patients with breast cancer, providing proof of principle for the clinical utility of CDK inhibition. However, despite extensive research over the past decade, CDK4/6 inhibitors have so far achieved regulatory approval only in this setting. Nonetheless, recent studies refining the optimal use of these drugs have revealed new opportunities to extend their use in other tumour types. Most notably, new combinatorial approaches, particularly with targeted therapies such as HER2 and PI3K inhibitors, are expanding the therapeutic scope of CDK4/6 inhibitors, and insights into resistance mechanisms have driven the development of highly selective CDK2 inhibitors to treat refractory disease. Additionally, efforts to mitigate haematological toxicity have prompted next-generation CDK4-selective inhibitors. Finally, biomarkers, although still underdeveloped clinically, are beginning to inform patient selection. This Review highlights the changes that have occurred in the clinical use of CDK inhibitors since the first FDA approval 10 years ago and the prospects for realizing their broader potential in cancer therapy.</p>