An abundant and diverse set of commensal microbial communities covers the body's surfaces, collectively so-called microbiome. It has a functional impact on various immune processes and modulates many health-related processes, including autoimmunity. An active site of microorganism-host interplay is the intestinal mucosa. Growing evidence has helped us to learn how a specific microbiota composition and its functionality determine the intestinal barrier function and, furthermore, modulate pro-inflammatory and anti-inflammatory immune mechanisms in remote organs. In addition, the microbial composition of the skin is important for the functionality of the skin barrier and autoimmune skin diseases. Here, we review the importance of the microbiome for the local and systemic immune system and how a disturbed microbiome-host interaction can affect the development and progression of autoimmune diseases. Understanding these associations will help to unravel new diagnostic and therapeutic approaches for those diseases.