The article reviews the role of cell cycle proteins in cancer and the rationale for targeting them in cancer therapy. It highlights that while some cell cycle proteins are not essential for proliferation in non-transformed cells, many cancers are uniquely dependent on these proteins, making them selectively sensitive to their inhibition. The review focuses on proteins that directly regulate cell cycle progression, such as cyclin-dependent kinases (CDKs) and the retinoblastoma protein (RB). It discusses the biology of the CDK4/CDK6-RB pathway, including the mechanisms by which these proteins promote cell cycle progression and their role in cancer. The article also covers the development and clinical success of CDK4/CDK6-selective inhibitors, such as palbociclib, ribociclib, and abemaciclib, which have shown promising results in various cancer types. Additionally, it explores the potential of targeting other cell cycle proteins, including DNA damage checkpoint kinases (CHK1 and WEE1), Polo-like kinases (PLK1), and Aurora kinases (Aurora A and Aurora B). The article emphasizes the importance of identifying predictive biomarkers to optimize the use of these inhibitors in clinical settings.The article reviews the role of cell cycle proteins in cancer and the rationale for targeting them in cancer therapy. It highlights that while some cell cycle proteins are not essential for proliferation in non-transformed cells, many cancers are uniquely dependent on these proteins, making them selectively sensitive to their inhibition. The review focuses on proteins that directly regulate cell cycle progression, such as cyclin-dependent kinases (CDKs) and the retinoblastoma protein (RB). It discusses the biology of the CDK4/CDK6-RB pathway, including the mechanisms by which these proteins promote cell cycle progression and their role in cancer. The article also covers the development and clinical success of CDK4/CDK6-selective inhibitors, such as palbociclib, ribociclib, and abemaciclib, which have shown promising results in various cancer types. Additionally, it explores the potential of targeting other cell cycle proteins, including DNA damage checkpoint kinases (CHK1 and WEE1), Polo-like kinases (PLK1), and Aurora kinases (Aurora A and Aurora B). The article emphasizes the importance of identifying predictive biomarkers to optimize the use of these inhibitors in clinical settings.