Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However, Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid, and brain tumors. This broad protumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. In this review, we discuss the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate, and disseminate to secondary organs, as well as resistance to chemotherapies. We subsequently discuss existing and new strategies for targeting Cdk5 and its downstream mechanisms as anticancer treatments.