Genome-wide association and whole genome sequencing studies have identified numerous genetic loci contributing to risk for type 2 diabetes mellitus (T2DM) and variation in T2DM-related traits. The most recent sequencing studies have revealed that genetic variation contributing to T2DM risk generally speaking have relatively small effect regardless of allele frequency, with some exceptions. It is noteworthy that most of these loci represent the “detectable” loci that are likely to be linkage disequilibrium with “the” functional loci. Thus, additional fine-mapping studies will be necessary to identify the latter. Furthermore, the vast majority of identified loci fall within non-coding regions of the genome, suggesting that additional studies detailing the molecular mechanisms of gene regulation and expression will be necessary to fully understand the implications of genetic variation in the pathogenesis of T2DM. We will review what has been learned from human genomic analysis and discuss its implications in the pathogenesis of type 2 diabetes. Physiologic analyses from large-scale consortia, such as MAGIC, will be review along with our own studies in Mexican Americans from the BetaGene Study. We will also review how genetic information might be translated into clinical care. In particular, we will used the example of peroxisome proliferator-activated receptor-γ (PPARG) to illustrate how clinicians might leverage genetic information for clinical care.