Senile plaques (SP) are complicated lesions composed of diverse amyloid peptides and associated molecules, degenerating neuronal processes,a nd reactive glia. Evidence suggests that diffuse, neurocentric amyloid deposits evolve over time with formation of discrete niduses that eventually become neuritic SP. The evidence for differential amyloid precursor protein metabolism that may favor deposition of A beta 17-42 in this early, possibly aging-related lesion is discussed. This latter molecule, also known as P3, may represent a benign form of amyloid, since it lacks domains associated with activation and recruitment of glia to SP. Subsequent to deposition of A beta 1-42 and then growth of the amyloid with precipitation of soluble A beta 1-40, in an Alzheimer disease-specific process, SP increasingly become associated with activated microglia and reactive astrocytes. In response to interaction with amyloid peptides and possibly glycated proteins, microglia and astrocytes produce a number of molecules that may be locally toxic to neuronal processes in the vicinity of SP, including cytokines, reactive oxygen and nitrogen intermediates, and proteases. They also produce factors that lead to their reciprocal activation and growth, which potentiate a local inflammatory cascade. Paired helical filament- (PHF) type neurites appear to be associated with SP only in so far as neurofibrillary degeneration has progressed to affect neurons in those regions where the plaque forms. Thus, PHF-type neurites are readily apparent in SP in the amygdala at an early stage, while they are late in primary cortices and never detected in cerebellar plaques; where only dystrophic neurites are detected. If the various stages of SP pathogenesis can be further clarified, it may be possible to develop rational approaches to therapy directed at site-, cell type-, and stage-specific interventions. Although controlling the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss, which is considered to be the proximate cause of the clinical dementia syndrome.