CAPN10, which encodes the cysteine protease calpain 10, was the first type 2 diabetes mellitus (T2DM) susceptibility gene identified through a genome-wide scan followed by positional cloning. A haplotype combination comprising three intronic CAPN10 single-nucleotide polymorphisms (UCSNP-43, -19, and -63) was associated with increased risk of T2DM in the population in which linkage was first found. Follow-up studies have been published from a wide range of populations; some confirm the original finding, but some do not. The exact function of calpain 10 remains to be determined, but it has been implicated both in glucose transporter 4 translocation to the cell membrane, regulation of pancreatic insulin secretion, and pancreatic beta-cell apoptosis. This article reviews the genetic evidence for the association between CAPN10 and T2DM. The latest understanding of the biologic function of calpain 10 is discussed, along with results from recent genome-wide association studies that have failed to put CAPN10 among the top signals.