The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimers disease (AD). On the basis of this hypothesis, inhibition of amyloid β-protein (Aβ) generation and aggregation, enhancement of extracellular Aβ removal, and Aβ vaccination are currently under investigation. Intracellular Aβ may be even more important than extracellular Aβ, since intraneuronal Aβ accumulation commonly precedes extracellular Aβ deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Aβ such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic Aβ42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, Aβ-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular Aβ42. Therefore, intraneuronal Aβ represents an alternative therapeutic target. While inhibition of Aβ production and anti-Aβ immunotherapies are likely to attenuate both intraneuronal and extracellular Aβ toxicity, more specific antiintraneuronal Aβ therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular Aβ and advocate intracellular Aβ as an important therapeutic target in AD.