Microdissection methods have been developed for isolating drusen and Bruch's membrane from human eyes. Comparative proteomic studies of these isolates from normal and AMD donors were pursued for clues to the biochemical pathways involved in the pathogenesis of AMD. A total of 129 potential drusen proteins were identified by LC MS/MS and immunocytochemical analyses have confirmed drusen localization for approximately 16% of the proteins. The most common drusen proteins appear to be TIMP-3, clusterin, vitronectin and serum albumin. Western blot analysis suggests that carboxyethyl pyrrole-protein adducts derived from docosahexaenoate-containing lipids are more abundant in AMD than in normal tissues. Abnormal protein cross-links and advanced glycation end products were also observed in drusen and Bruch's membrane. Lipid oxidation products and oxidative protein modifications may be causally involved in drusen formation and Bruch's membrane thickening.