Autoimmune disease has traditionally been thought to be due to the impact of environmental factors on genetically susceptible individuals causing immune dysregulation and loss of tolerance. However, recent literature has highlighted the importance of the microbiome, (a collective genome of microorganisms in a given niche) in immune homeostasis. Increasingly, it has been recognized that disruptions in the commensal microflora may lead to immune dysfunction and autoimmunity. This review summarizes recent studies investigating the interplay between the microbiome and immune-mediated organ-specific diseases. In particular, we review new findings on the role of the microbiome in inflammatory bowel disease, celiac disease, psoriasis, rheumatoid arthritis, type I diabetes, and multiple sclerosis.