The cerebral accumulation of β-amyloid protein (Aβ) is thought to play a key role in the molecular pathology of Alzheimer’s disease (AD). Recent evidence indicates that both β-secretase and γ-secretase, the membrane-associated proteases directly involved in the generation of Aβ from its precursor, amyloid precursor protein (APP), are localized to cholesterol-rich membrane microdomains termed lipid rafts. This underscores the significance of lipid rafts in the amyloidogenic processing of APP. In the present mini-review, I summarize recent research developments that shed light on the association of β-secretase and γ-secretase with lipid rafts, and discuss their implications for the pathology and therapeutics of AD.