Small heat shock proteins function as chaperones by binding unfolding substrate proteins in an ATP-independent manner to keep them in a folding-competent state and to prevent irreversible aggregation. They play crucial roles in diseases that are characterized by protein aggregation, such as neurodegenerative and neuromuscular diseases, but are also involved in cataract, cancer, and congenital disorders. For this reason, these proteins are interesting therapeutic targets for finding molecules that could affect the chaperone activity or compensate specific mutations. This review will give an overview of the available knowledge on the structural complexity of human small heat shock proteins, which may aid in the search for such therapeutic molecules.