Calpain-10 (CAPN10) is the first diabetes gene to be identified through a genome scan. Many investigators, but not all, have subsequently found associations between CAPN10 polymorphism and type 2 diabetes (T2D) as well as insulin action, insulin secretion, aspects of adipocyte biology and microvascular function. However, this has not always been with the same single nucleotide polymorphism (SNP) or haplotype or the same phenotype, suggesting that there might be more than one disease-associated CAPN10 variant and that these might vary between ethnic groups and the phenotype under study. Our understanding of calpain-10 physiological action has also been greatly augmented by our knowledge of the calpain family domain structure and function, and the relationship between calpain-10 and other calpains is discussed here. Both genetic and functional data indicates that calpain-10 has an important role in insulin resistance and intermediate phenotypes, including those associated with the adipocyte. In this regard, emerging evidence would suggest that calpain-10 facilitates GLUT4 translocation and acts in reorganization of the cytoskeleton. Calpain-10 is also an important molecule in the β-cell. It is likely to be a determinant of fuel sensing and insulin exocytosis, with actions at the mitochondria and plasma membrane respectively. We postulate that the multiple actions of calpain-10 may relate to its different protein isoforms. In conclusion, the discovery of calpain-10 by a genetic approach has identified it as a molecule of importance to insulin signaling and secretion that may have relevance to the future development of novel therapeutic targets for the treatment of T2D. Copyright © 2005 John Wiley & Sons, Ltd.