The molecular composition of the postsynaptic density is modified during synaptic plasticity, which forms the molecular basis of learning and memory. Such changes in synaptic composition depends in part on the intricate regulation of phosphorylation of specific proteins via different protein kinases, including a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). However, the mechanisms underlying the involvement of Cdk5 in neural plasticity remain elusive. Recently, the identification of a number of synaptic proteins as substrates or interacting proteins with Cdk5 provides important clues on how this kinase modulates the efficacy of synaptic transmission. In this review, we summarize the recent findings to illustrate the multi-faceted roles of Cdk5 in synaptic plasticity through affecting dendritic spine formation, ion channel conductance, protein expression, and transcription in the postsynaptic neurons. Importantly, dysregulation of Cdk5 has been linked to Alzheimer's disease, which involves perturbations in synaptic functions and memory formation. Understanding the mechanisms by which Cdk5 regulates synaptic plasticity may therefore provide important insights in the design of novel therapeutic strategies for neurodegenerative diseases.