Autoimmune diseases are complex illnesses in which the body’s immune system attacks its own healthy tissues. These diseases, which can be fatal, gravely impact the quality of life of those afflicted by them with no cure currently available. The exact etiology of autoimmune diseases is not completely clear. Biomedical research has revealed that both genetic and environmental factors contribute to the development and progression of these diseases. Nevertheless, genetic and environmental factors alone cannot explain a large proportion of cases, leading to the possibility that the two factors interact in driving disease onset. Understanding how genetic and environmental factor influence host physiology in a manner that leads to the development of autoimmune diseases can reveal the mechanisms by which these diseases manifest, and bring us closer to finding a cure for them. In this chapter, we will review the current research of genetic/environmental interactions that contribute to development of autoimmune diseases, with an emphasis on interactions between the host and the multitudes of microbes that inhabit it, the microbiota.