Spondyloarthritis (SpA) describes the group of inflammatory diseases characterized by inflammation within axial joints and/or peripheral arthritis, enthesitis, and dactylitis. Disease development is strongly determined by genes and particularly associated with the presence of HLA-B27. Transgenic expression in animal models leads to induction of a SpA-like disease, suggesting a direct effect of HLA-B27 on disease development. Genome-wide association studies in SpA patients have identified further associations between polymorphisms in genes with an immune function, in particular in genes controlling the interleukin (IL)-23/IL-17 signaling pathway. The efficacy of IL-17 inhibitors in SpA patients underscores the impact of this pathway in this disease. Microscopic gut inflammation or chronic inflammatory bowel disease is found in the majority of patients with SpA, suggesting a pathogenic impact of commensal microbiota. In histopathologic examinations of axial manifestations, replacement of the subchondral bone marrow by granulation tissue with bone destructive and reparative properties is found. The mechanisms governing how genetic predisposition and gut inflammation promote inflammatory reactions at sites of mechanical stress is a matter of current research.