Small heat shock proteins (sHSPs) function as molecular chaperones, preventing stress induced aggregation of partially denatured proteins and promoting their return to native conformations when favorable conditions pertain. Sequence similarity between sHSPs resides predominately in an internal stretch of residues termed the α‐crystallin domain, a region usually flanked by two extensions. The poorly conserved N‐terminal extension influences oligomer construction and chaperone activity, whereas the flexible C‐terminal extension stabilizes quaternary structure and enhances protein/substrate complex solubility. sHSP polypeptides assemble into dynamic oligomers which undergo subunit exchange and they bind a wide range of cellular substrates. As molecular chaperones, the sHSPs protect protein structure and activity, thereby preventing disease, but they may contribute to cell malfunction when perturbed. For example, sHSPs prevent cataract in the mammalian lens and guard against ischemic and reperfusion injury due to heart attack and stroke. On the other hand, mutated sHSPs are implicated in diseases such as desmin‐related myopathy and they have an uncertain relationship to neurological disorders including Parkinson's and Alzheimer's disease. This review explores the involvement of sHSPs in disease and their potential for therapeutic intervention.