Here, we not only show that central Hh signaling components are expressed in human intestinal CD4+ T cells and that expression of SMO and GLI3 is upregulated in patients with IBD correlating with Th17 infiltration, but also demonstrate that clinically approved Hh inhibitor vismodegib specifically and potently inhibits Th17 polarization in vivo. Here, SMO is linked to inflammatory bowel disease.