The mucosal immune system entails the immune cells located in the body's mucosal surfaces and their mediators. Its function is to balance immune responses to pathogens and tolerance to harmless antigens. Treatment of autoimmune diseases is complicated by adverse events caused by suppression of systemic immunity by immunosuppressive medication. Targeting the mucosal immune system specifically in treating autoimmune diseases could circumvent systemic immune suppression and thereby reduce infection risk. This systematic review aims to provide an overview of pharmaceutical targets in the mucosal immune system, as a starting point in the search for new treatments for extra-intestinal auto-immune diseases. Preclinical and clinical studies were included and categorized into eight target categories: ‘immune cells’, ‘signal transduction’, ‘inflammatory mediators’, ‘antibodies’, ‘microbiome’, ‘tolerance and mucosal vaccination’, ‘intestinal barrier’ and ‘other’. Studies investigating the most promising targets, namely mucosal-associated invariant T cells (MAIT cells) and tolerance induction by mucosal vaccination, are described in more detail. MAIT cells have been shown to play a role in the pathophysiology of various auto-immune diseases, particularly in multiple sclerosis (MS). Although the role of these cells has not yet been established fully, mouse studies show that the antagonism of MAIT cells has the potential to be used in the treatment of auto-immune diseases. Mucosal vaccination has demonstrable effects on the immune system, but treatment regimens and antigens must be improved to demonstrate clinical effects more extensively. This systematic review was registered in PROSPERO under number CRD42023421093.