Apoptotic neuronal cell death is the cardinal feature of aging and neurodegenerative diseases, but its mechanisms remain obscure. Caspases, members of the cysteine protease family, are known to be critical effectors in central nervous system cellular apoptosis. More recently, the calcium-dependent proteases, calpains, have been implicated in cellular apoptotic processes. Indeed, several members of the Bcl-2 family of cell death regulators, nuclear transcription factors (p53) and caspases themselves are processed by calpains. Progressive regional loss of neurons underlies the irreversible pathogenesis of various neurodegenerative diseases such as Alzheimer's disease in adult brain. Alzheimer's disease is characterized by extracellular plaques of amyloid–β peptide aggregates and intracellular neurofibrillary tangles composed of hyperphosphorylated tau leading to apoptotic cell death. In this review, we summarize the arguments showing that calpains modulate processes that govern the function and metabolism of these two key proteins in the pathogenesis of Alzheimer's disease. To conclude, this article reviews our understanding of calpain-dependent apoptotic neuronal cell death and the ability of these proteases to regulate intracellular signaling pathways leading to chronic neurodegenerative disorders such as Alzheimer's disease. Further research on these calpain-dependent mechanisms which promote or prevent cell apoptosis should help us to develop new approaches for preventing and treating neurodegenerative disorders.