Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Abnormalities in mitochondrial properties include impaired energy metabolism, defects in key respiratory enzyme activity/function, accumulation/generation of mitochondrial reactive oxygen species, and formation of membrane permeability transition pore. While the mechanisms underlying mitochondrial dysfunction remain incompletely understood, recent studies provide substantial evidence for the progressive accumulation of mitochondrial Abeta, which directly links to mitochondria-mediated toxicity. In this review, we describe recent studies addressing the following key questions: 1) Does Abeta accumulate in mitochondria of AD brain and AD mouse models? 2) How does Abeta gain access to the mitochondria? 3) If mitochondria are loaded with Abeta, do they develop similar evidence of dysfunction? 4) What are the mechanisms underlying mitochondrial Abeta-induced neuronal toxicity? and 5) What is the impact of interaction of mitochondrial Abeta with its binding partners (cyclophilin D and ABAD) on mitochondrial and neuronal properties/function in an Abeta milieu? The answers to these questions provide new insights into mechanisms of mitochondrial stress related to the pathogenesis of AD and information necessary for developing therapeutic strategy for AD.