Cell cycle proteins are promising targets in cancer therapy due to their role in uncontrolled proliferation in cancer cells. These proteins regulate the cell cycle, ensuring proper DNA replication and cell division. Targeting them can selectively inhibit cancer cells while sparing normal tissues. The review discusses the role of cell cycle proteins in cancer, the rationale for targeting them, and results of clinical trials, highlighting the potential of various inhibitors. The cell cycle is regulated by cyclin-dependent kinases (CDKs), which are controlled by cyclins and CDK inhibitors. CDK4/CDK6 and the retinoblastoma (RB) protein are critical for cell cycle progression. Mutations in these proteins are common in many cancers, making them attractive targets. CDK4/CDK6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have shown promise in clinical trials for various cancers, including breast cancer. These inhibitors induce cell cycle arrest and senescence in cancer cells, leading to tumor regression. Other cell cycle proteins, such as CDK2, CDK1, and the DNA damage checkpoint kinases CHK1 and WEE1, also play important roles in cancer. Inhibitors of these proteins, such as MK-8776 (CHK1 inhibitor) and AZD1775 (WEE1 inhibitor), have shown clinical activity in various cancers. Polo-like kinase (PLK1) inhibitors, like rigosertib and volasertib, and Aurora kinase inhibitors, such as alisertib, are also under investigation. The review emphasizes that while many cell cycle proteins are redundant in normal tissues, their continued expression is critical for tumor maintenance. This makes them attractive targets for cancer therapy. However, resistance to these inhibitors can develop, and further research is needed to identify predictive biomarkers for clinical response. Overall, targeting cell cycle proteins offers a promising approach for cancer therapy, with several inhibitors currently in clinical trials.Cell cycle proteins are promising targets in cancer therapy due to their role in uncontrolled proliferation in cancer cells. These proteins regulate the cell cycle, ensuring proper DNA replication and cell division. Targeting them can selectively inhibit cancer cells while sparing normal tissues. The review discusses the role of cell cycle proteins in cancer, the rationale for targeting them, and results of clinical trials, highlighting the potential of various inhibitors. The cell cycle is regulated by cyclin-dependent kinases (CDKs), which are controlled by cyclins and CDK inhibitors. CDK4/CDK6 and the retinoblastoma (RB) protein are critical for cell cycle progression. Mutations in these proteins are common in many cancers, making them attractive targets. CDK4/CDK6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have shown promise in clinical trials for various cancers, including breast cancer. These inhibitors induce cell cycle arrest and senescence in cancer cells, leading to tumor regression. Other cell cycle proteins, such as CDK2, CDK1, and the DNA damage checkpoint kinases CHK1 and WEE1, also play important roles in cancer. Inhibitors of these proteins, such as MK-8776 (CHK1 inhibitor) and AZD1775 (WEE1 inhibitor), have shown clinical activity in various cancers. Polo-like kinase (PLK1) inhibitors, like rigosertib and volasertib, and Aurora kinase inhibitors, such as alisertib, are also under investigation. The review emphasizes that while many cell cycle proteins are redundant in normal tissues, their continued expression is critical for tumor maintenance. This makes them attractive targets for cancer therapy. However, resistance to these inhibitors can develop, and further research is needed to identify predictive biomarkers for clinical response. Overall, targeting cell cycle proteins offers a promising approach for cancer therapy, with several inhibitors currently in clinical trials.