A definitive diagnosis of Alzheimer’s disease depends on postmortem analysis of brain tissue bearing the pathological hallmarks of the disease: plaques and tangles. Imaging techniques that allow visualization and characterization of these lesions in living animals permit a better understanding of the pathogenesis of the disease as well as paradigms for preventing or reversing the deposits. Multiphoton microscopy uses near infrared light that is benign to living tissue and penetrates more deeply than visible or UV light, permitting high-resolution imaging of these microscopic structures deep within the cortex of living transgenic mice over time. This in vivo imaging approach allows direct examination of the natural history of plaques and evaluation of antiplaque therapeutics in mouse models of the disease.