Recent knowledge supports the idea that early protein aggregates share basic structural features and are responsible for cytotoxicity underlying neurodegeneration; in most cases, early aggregate cytotoxicity apparently proceeds through similar molecular mechanisms and results in similar biochemical modifications. Data suggest that aggregate cytotoxicity may be considered a generic property of the oligomers preceding fibril appearance. Oligomers can interact with cell membranes, impairing their structural organization and destroying their selective ion permeability, eventually culminating with cell death. This process can be influenced by the physicochemical features and aggregation state of amyloids as well as by the physical and biochemical features of cell surfaces. The roles of synthetic and biological surfaces in affecting protein folding and misfolding, in speeding up aggregate nucleation, and as targets of aggregate toxicity is gaining consideration. Recent research has highlighted the involvement of surfaces as protein-misfolding chaperones and aggregation catalysts and their effects in these phenomena. NEUROSCIENTIST 13(5):519—531, 2007.