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Neurodegenerative diseases are caused by the progressive loss of specific neurons. The exact mechanisms of action of these diseases are unknown, and many studies have focused on pathways related to abnormal accumulation and processing of proteins, mitochondrial dysfunction, and oxidative stress leading to apoptotic death. However, a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration. The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms, including c-Jun N-terminal kinases, p38 mitogen-activated protein kinases, and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades; post-translational modifications such as Tau-phosphorylation; and DNA damage response. In all these events, implicated Cdk5, a proline-directed serine/threonine protein kinase, seems to be responsible for several cellular processes in neurons including axon growth, neurotransmission, synaptic plasticity, neuronal migration, and maintenance of neuronal survival. However, under pathological conditions, Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons. Thus, Cdk5 hyperactivation, by its physiologic activator p25, hyper-phosphorylates downstream substrates related to neurodegenerative diseases. This review summarizes factors such as oxidative stress, DNA damage response, signaling pathway disturbance, and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons. It also describes how all these factors are linked to a greater or lesser extent with Cdk5. Thus, it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease by cell cycle activation.