The article reviews the history and future of targeting cyclin-dependent kinases (CDKs) in cancer therapy. CDKs are critical regulatory enzymes that control the cell cycle, and their dysregulation is a common feature of cancer. The authors discuss the biology of CDKs, the rationale for therapeutically targeting them, and the historical clinical results of CDK inhibitors. They highlight the importance of high selectivity for specific CDKs, particularly CDK4 and CDK6, in combination with patient stratification, for achieving substantial clinical activity. The article also covers the development of pan-CDK inhibitors and second-generation inhibitors, emphasizing the challenges and limitations of non-selective inhibitors. The authors emphasize the need for selective CDK4/6 inhibitors, which have shown promise in clinical trials, especially in combination with hormone therapy for ER-positive breast cancer. They discuss biomarker strategies for selecting patients likely to benefit from CDK4/6 inhibition and the potential for combining these inhibitors with other targeted therapies. Finally, the article concludes by outlining the future prospects for CDK4/6 inhibitors in cancer treatment.The article reviews the history and future of targeting cyclin-dependent kinases (CDKs) in cancer therapy. CDKs are critical regulatory enzymes that control the cell cycle, and their dysregulation is a common feature of cancer. The authors discuss the biology of CDKs, the rationale for therapeutically targeting them, and the historical clinical results of CDK inhibitors. They highlight the importance of high selectivity for specific CDKs, particularly CDK4 and CDK6, in combination with patient stratification, for achieving substantial clinical activity. The article also covers the development of pan-CDK inhibitors and second-generation inhibitors, emphasizing the challenges and limitations of non-selective inhibitors. The authors emphasize the need for selective CDK4/6 inhibitors, which have shown promise in clinical trials, especially in combination with hormone therapy for ER-positive breast cancer. They discuss biomarker strategies for selecting patients likely to benefit from CDK4/6 inhibition and the potential for combining these inhibitors with other targeted therapies. Finally, the article concludes by outlining the future prospects for CDK4/6 inhibitors in cancer treatment.