The small heat-shock molecular chaperone proteins (sHsps) are one of the cell’s first-lines of defence against protein aggregation and therefore play a vital role in maintaining protein homeostasis (proteostasis) [1]. Despite this, the precise mechanism by which they function as chaperones remains unresolved. We and others have shown that the sHsps are potent inhibitors of the (amyloid) fibrillar aggregation of proteins, a process which is associated with diseases that include Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Moreover, the sHsps interact with a variety of species formed during this aggregation process, from monomers to the mature fibrils. In each case they act to prevent the cellular toxicity that is associated with amyloid fibril formation. They therefore represent attractive therapeutic targets for the treatment of diseases associated with protein aggregation. Recently our work has focussed on defining the key region(s) in sHsps responsible for this chaperone activity. We have demonstrated that the core alpha-crystallin domain has chaperone activity comparable to that of the full-length protein [2]. Thus, this sHsp core domain is a potent inhibitor of amyloid fibril formation and, by inhibiting its aggregation, effectively reduces the cytotoxicity of amyloid-β peptide, the aggregation of which is associated with Alzheimer’s disease. Our experiments therefore identify a novel, small and highly structured ‘functional unit’ of sHsps which potentially enables more rational design of sHsp activators and inhibitors.