With the advent of transgenic mouse models expressing cortical amyloid pathology, the potential to study its progression in an intact brain has been realized. Multiphoton microscopy provides a non-destructive means of imaging with micron resolution up to 500 m deep into the cortex. We detail a surgical procedure and discuss a multiphoton imaging approach that allows for labeling and chronic visualization of amyloid-ß deposits through a cranial window. The ability to monitor these hallmarks of Alzheimer's disease enables studies aimed at evaluating the efficacy of treatment and prevention strategies.