For the better part of the past two decades, studies on the molecular, biochemical and cellular mechanisms of Alzheimer disease have focused on amyloid-beta protein, the major proteinaceous component of senile plaques. In fact, the Amyloid Cascade Hypothesis has come to dominate the field both in terms of proposed disease mechanism as well as potential for therapeutic intervention. In this review, we look at the Amyloid Cascade Hypothesis from the perspective of pathology, cell biology, and genetics. In all cases, alternate interpretations of old data as well as new evidence indicates that amyloid-beta, far from being the harbinger of disease, actually occurs secondary to more fundamental pathological changes and may even play a protective role in the diseased brain. These findings bring into serious doubt the validity of the Amyloid Cascade Hypothesis as the central cause of Alzheimer disease and, consequently, the potential usefulness of therapeutic targets against amyloid-beta.