Preventing and treating Alzheimer's disease require understanding the aggregation of amyloid beta 1-42 (A beta(1-42)) to give oligomers, protofibrils, and fibrils. Here we describe footprinting of A beta(1-42) by hydroxyl radical-based fast photochemical oxidation of proteins (FPOP) and mass spectrometry (MS) to monitor the time-course of A beta(1-42) aggregation. We resolved five distinct stages characterized by two sigmoidal behaviors, showing the time-dependent transitions of monomers-paranuclei-protofibrils-fibrillar aggregates. Kinetic modeling deciphering the amounts and interconversion of the dominant A beta(1-42) species. Moreover, the irreversible footprinting probe provides insights into the kinetics of oligomerization and subsequent fibrillar growth by allowing the conformational changes of A beta(1-42) at subregional and even amino-acid-residue levels to be revealed. The middle domain of A beta(1-42) plays a major role in aggregation, whereas the N-terminus retains most of its solvent-accessibility during aggregation, and the hydrophobic C-terminus is involved to an intermediate extent. This approach affords an in situ, real-time monitoring of the solvent accessibility of A beta(1-42) at various stages of oligomerization, and provides new insights on site-specific aggregation of A beta(1-42) for a sample state beyond the capabilities of most other biophysical methods.