Background: The relatively common co-occurrence of type 1 diabetes (T1D) and celiac disease (CD) suggests these disorders share common pathogenic etiologies. Summary: T1D and CD are strongly linked to closely related high-risk human lymphocyte antigens (HLA-DR-DQ). High-risk HLA molecules bind specific fragments of gluten or the islet self-antigen(s) and present these antigens to antigen-responsive T cells. In an appropriate proinflammatory environment, the autoimmune response results in destruction of the intestinal enterocyte and/or the pancreatic beta cell. Environmental factors have been implicated in the etiology of T1D and CD because (1) identical twins are only partially concordant for these disorders and (2) incidence rates of T1D and CD have been steadily rising for decades. Prospective studies in infants genetically predisposed to T1D and CD showed that antibody positivity to both disorders begins in the first 1–3 years of life. Viral infections and early exposure to gluten or cow’s milk in the infant diet have been implicated in disease pathogenesis. However, delaying introduction of gluten in the infant diet until 12 months of age had no impact on the development of islet or celiac autoimmunity. Weaning nursing infants to hydrolyzed infant formula had no impact on the development of T1D. Viral infections have been suspected of playing a role in T1D pathogenesis for decades. A large international prospective study (TEDDY) has shown increased risk of T1D autoimmunity particularly when >5 respiratory infections or febrile infections have occurred in the 9 months preceding the appearance of islet antibodies. Provocative data in animal models of T1D suggest the microbiome may play an important role in the pathogenesis of T1D. Breastfeeding, diet, infections, antibiotics, and method of birth alter the composition of the microbiome. Human data indicate subtle differences in the microbiome of children with T1D autoimmunity, while intestinal dysbiosis has been clearly demonstrated in CD. Alterations of the integrity of the intestinal mucosa plays an important role in the pathogenesis of CD, and the NOD mouse model suggests an important role of a leaky intestinal epithelium in T1D as well. Key Message: Immunogenetics and the environment are closely interrelated in the pathogenesis of T1D and CD. Large well-designed prospective studies in at-risk populations informed by scientifically rigorous studies in animal models are likely to have the greatest impact on our understanding of the complex pathogenesis of these detrimental autoimmune disorders.