CDK5 is a proline-directed serine/threonine kinase that plays a regulatory role in the phosphorylation/dephosphorylation of the eukaryotic cell cycle. Unlike other cyclin-dependent kinases, CDK5 is not activated by cyclins but by p35/p25 proteins, which are highly expressed in the nervous system. CDK5 controls key neural functions such as cytoskeletal structure and dynamics, axonal guidance, neuronal migration, cell adhesion, synaptic transmission, and membrane transport in the nervous system. The absence or dysfunction of CDK5 can lead to neurodevelopmental disorders, while its overactivation can lead to neuronal death and is considered a key factor in Alzheimer's disease. CDK5 and its activator p35 are also expressed in most non-neural tissues, regulating various physiological functions, including hematopoietic cell differentiation, immune response, lymphatic valve formation, myogenesis, melanogenesis, insulin levels, cell migration, wound healing, invasion, survival, and angiogenesis. Abnormal activity of CDK5 is closely related to the pathological changes of various neurodegenerative diseases, including Alzheimer's disease. The role of CDK5 in cancer is also increasingly being studied, with abnormal expression or activation of its activators (especially p35) found in various human cancers, including colorectal, breast, lung, ovarian, prostate, pancreatic, melanoma, and hematological malignancies.