In the past decade, the discovery and characterization of cyclin-dependent kinases (CDKs), the engine cores of the cell cycle machinery, have advanced our understanding of the cell cycle. Both positive and negative regulators of CDKs have been characterized, accelerating the important research to unravel the mechanisms of the cell cycle disease--cancer. Cancer can originate from overexpression of positive regulators, such as cyclins, or from underexpression of negative regulators, such as CDK inhibitors (CKIs). CKIs are the focus of much cancer research because they are capable of controlling cell cycle proliferation--the Holy Grail for cancer treatment. CDKs can be inactivated by several mechanisms:, (i) by association with CKIs including p16 (INK4a), p15 (INK4b), p21 (Cip1), p27 (Kip1), and p57 (Kip2), (ii) by disassociation from their cyclin regulatory unit, (iii) by dephosphorylation of a conserved threonine residue in the T-loop, and (iv) by adding inhibitory phosphate. Here we discuss what is known about each mechanism with a hope that these insights will become useful in developing strategies to eliminate cancer in the future.