Small heat shock proteins (sHSPs) are key members of the HSP superfamily that are ubiquitous among all organisms. The amino acid sequences of the sHSPs are not as highly conserved as the larger HSPs but it comprises a characteristic α-crystallin domain (ACD). The mammalian sHSP family, now referred to as the HSPB family, includes 11 members: HSP27/HSPB1, MKBP (myotonic dystrophy protein kinase-binding protein)/HSPB2, HSPB3, alphaA-crystallin / HSPB4, alphaB-crystallin/HSPB5, HSP20/HSPB6, cvHSP (cardiovascular heat shock protein)/HSPB7, HSP22/HSPB8, HSPB9, ODF1 (outer dense fi ber protein)/ HSPB10, and HSPB11. They have been reported to have a wide range of cellular functions, including endowing cells with thermotolerance and acting as molecular chaperones. Because of these functions, sHSPs can participate in a large number of fundamental cellular processes such as controlling protein folding, F-actindependent processes, cytoprotection/anti-apoptosis, differentiation, cell proliferation, and gene expression, and thereby are involved in many pathological diseases, such as neurodegenerative diseases, cancer, and cardiovascular diseases. Genetic mutation or variations of sHSPs genes may change their expression levels and affect protein functions, thus contributing to cell malfunction especially during stress.Here we examined the current reports regarding the mutations or variations of sHSPs genes, and we analyzed their associations with the development, progression, and prognosis of some human diseases. We also addressed the biological functions for the potential causal sHSPs variations and discussed their possible implications in human diseases.