Cyclin-dependent kinases (Cdks) are a family of proline-directed Ser/Thr kinases known for their role in the control of cell cycle progression. In 1992, this family was joined by Cdk5, which is an atypical member in that it uses its own activators and is multifunctional, playing important regulatory roles in multiple cellular functions. Here, we review the structure of Cdk5 and its various mechanisms of activation within the context of the Cdk family. We also address the functional significance of the numerous and varied targets of Cdk5 within pathways that control the organization of the cytoskeleton and focal adhesions, signaling cascades, membrane dynamics and function, cell metabolism, cycle arrest in postmitotic cells, gene transcription and cell survival, all within the context of the adaptation of cells and life systems to changing internal and external environments.