Previous studies have shown that β-amyloid (Aβ) peptides are neurotoxic. Recent data suggest that neurons undergoing Aβ-induced cell death exhibit characteristics that correspond to the classical features of apoptosis, suggesting that these cells may initiate a program of cell death. This chapter explores the criteria and precautions that must be applied to evaluate mechanisms of cell death in vitro and in vivo, discusses the evidence supporting an apoptotic mechanism of cell death in response to Aβ in cultured neurons, and describes potential correlations for these findings in the Alzheimer's disease brain. In addition, cellular signaling pathways that may be associated with apoptosis in response to Aβ are examined, and support for apoptosis as a mechanism of cell death for other neurodegeneration-inducing stimuli (e.g., oxidative injury) is described. The connection of multiple stimuli that induce neuronal cell death to an apoptotic mechanism suggests that apoptosis could play a central role in neurodegeneration in the brain.