The chapter discusses the role of cyclin-dependent kinases (CDKs) and their inhibitors (CKIs) in regulating the G1 phase of the mammalian cell cycle. CDKs, particularly those containing cyclin D or E, are crucial for progression through the G1 phase and initiation of DNA synthesis. CKIs, such as INK4 proteins and Cip/Kip proteins, serve as negative regulators by inhibiting CDKs. The INK4 proteins, including p16INK4a, p15INK4b, p18INK4c, and p19INK4d, specifically target CDK4 and CDK6, while the Cip/Kip proteins, including p21Cip1, p27Kip1, and p57Kip2, have broader targets including CDK2, CDK4, and CDK6. The chapter highlights the complex interactions between CKIs and CDKs, emphasizing that CKIs can both inhibit and sequester CDKs. For example, INK4 proteins can bind to and inhibit CDK4, while Cip/Kip proteins can sequester CDK4 and promote its activation by binding to cyclin D. The assembly of active cyclin D-CDK4 complexes is facilitated by Cip/Kip proteins, which also help in the nuclear import of these complexes. The chapter also discusses the role of Rb protein in controlling the G1/S transition by regulating the activity of E2F transcription factors. Rb inactivation by CKIs allows E2F to activate genes required for DNA synthesis, leading to cell cycle progression. The loss of Rb function or the inactivation of CKIs can lead to uncontrolled cell proliferation, as seen in cancer cells. Finally, the chapter explores the implications of CKI loss or gain in cancer, noting that while disruption of Rb or p16 function is common in cancer, complete loss of Cip/Kip function has not been observed. The chapter concludes by discussing the complex interplay between CKIs and CDKs in regulating the cell cycle and their potential roles in cancer development.The chapter discusses the role of cyclin-dependent kinases (CDKs) and their inhibitors (CKIs) in regulating the G1 phase of the mammalian cell cycle. CDKs, particularly those containing cyclin D or E, are crucial for progression through the G1 phase and initiation of DNA synthesis. CKIs, such as INK4 proteins and Cip/Kip proteins, serve as negative regulators by inhibiting CDKs. The INK4 proteins, including p16INK4a, p15INK4b, p18INK4c, and p19INK4d, specifically target CDK4 and CDK6, while the Cip/Kip proteins, including p21Cip1, p27Kip1, and p57Kip2, have broader targets including CDK2, CDK4, and CDK6. The chapter highlights the complex interactions between CKIs and CDKs, emphasizing that CKIs can both inhibit and sequester CDKs. For example, INK4 proteins can bind to and inhibit CDK4, while Cip/Kip proteins can sequester CDK4 and promote its activation by binding to cyclin D. The assembly of active cyclin D-CDK4 complexes is facilitated by Cip/Kip proteins, which also help in the nuclear import of these complexes. The chapter also discusses the role of Rb protein in controlling the G1/S transition by regulating the activity of E2F transcription factors. Rb inactivation by CKIs allows E2F to activate genes required for DNA synthesis, leading to cell cycle progression. The loss of Rb function or the inactivation of CKIs can lead to uncontrolled cell proliferation, as seen in cancer cells. Finally, the chapter explores the implications of CKI loss or gain in cancer, noting that while disruption of Rb or p16 function is common in cancer, complete loss of Cip/Kip function has not been observed. The chapter concludes by discussing the complex interplay between CKIs and CDKs in regulating the cell cycle and their potential roles in cancer development.