The article reviews the history and future of targeting cyclin-dependent kinases (CDKs) in cancer therapy. CDKs are critical regulators of the cell cycle, and their dysregulation is associated with tumorigenesis. Despite early optimism, clinical development of CDK inhibitors has been challenging due to limited selectivity and off-target effects. Recent advances in CDK inhibitor development, particularly for CDK4 and CDK6, have shown promising results in clinical trials. These inhibitors selectively target the CDK4/6-RB pathway, which is crucial for cell cycle progression. The article discusses the biology of CDKs, their role in cancer, and the challenges in developing effective CDK inhibitors. It also highlights the importance of patient selection and biomarker strategies in improving clinical outcomes. The future of CDK inhibitors in cancer therapy depends on further research into their mechanisms of action, combination therapies, and the development of highly selective agents. The article concludes that the potential of CDK inhibitors in cancer therapy is now being realized, following the Nobel Prize-winning discoveries of CDKs.The article reviews the history and future of targeting cyclin-dependent kinases (CDKs) in cancer therapy. CDKs are critical regulators of the cell cycle, and their dysregulation is associated with tumorigenesis. Despite early optimism, clinical development of CDK inhibitors has been challenging due to limited selectivity and off-target effects. Recent advances in CDK inhibitor development, particularly for CDK4 and CDK6, have shown promising results in clinical trials. These inhibitors selectively target the CDK4/6-RB pathway, which is crucial for cell cycle progression. The article discusses the biology of CDKs, their role in cancer, and the challenges in developing effective CDK inhibitors. It also highlights the importance of patient selection and biomarker strategies in improving clinical outcomes. The future of CDK inhibitors in cancer therapy depends on further research into their mechanisms of action, combination therapies, and the development of highly selective agents. The article concludes that the potential of CDK inhibitors in cancer therapy is now being realized, following the Nobel Prize-winning discoveries of CDKs.