Alzheimer's disease (AD) is the most common neurodegenerative disease associated with aging. One important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major components are small peptides called beta-amyloid (Abeta) that are derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta-secretase and gamma-secretase. Because of the critical role of Abeta in the pathogenesis of AD, unraveling the cellular and molecular events underlying APP/Abeta metabolism has been and remains, of paramount importance to AD research. In this article we will focus on the regulation of APP metabolism leading to Abeta generation. We will review current knowledge of the secretases (alpha-, beta-, and gamma-secretases) involved in APP processing and various molecular and cellular mechanisms underlying intracellular trafficking of APP, which is a highly regulated process and whose disturbance has direct impacts on the production of Abeta.