Uncontrolled cell division is a defining characteristic of cancer cells. Cyclin-dependent kinases (Cdks) are critical regulators of cell cycle progression. Deregulated Cdk activities as a result of gene amplification, translocation, or point mutations of Cdks or cyclins, have been reported in a majority of human cancers. These kinases, therefore, represent potential therapeutic targets for the treatment of cancer. In this review, we offer an overview of Cdk functions in driving cell cycle progression and transcriptional regulation, a highlight of the DNA damage checkpoints, and an outline of the most relevant Cdk inhibitors currently in clinical trials with an emphasis on the Cdk inhibitors used for treatment of multiple myeloma.