Alzheimer's disease (AD), which is predicted to affect 1 in 85 persons worldwide by 2050, results in progressive loss of neuronal functions, leading to impairments in memory and cognitive abilities. As being one of the major neuropathological hallmarks of AD, senile plaques mainly consist of amyloid-beta (A beta) peptides, which are derived from amyloid precursor protein (APP) via the sequential cleavage by beta- and gamma-secretases. Although the over- production and accumulation of A beta peptides are at the center of AD research, the new discoveries point out to the complexity of the disease development. In this respect, it is crucial to understand the processing and the trafficking of APP, the enzymes involved in its processing, the cleavage products and their therapeutic potentials. This review summarizes the salient features of APP processing focusing on APP, the canonical secretases as well as the novel secretases and the cleavage products with an update of the recent developments. We also discussed the intracellular trafficking of APP and secretases in addition to their potential in AD therapy.