Here, we review histopathologic studies of the cellular and molecular pathways of spondyloarthritis (SpA) synovial inflammation. In contrast with lymphocytes, specific macrophage subsets and polymorphonuclear cells selectively increase in SpA synovitis, correlate with global disease activity, decrease rapidly upon effective treatment with tumor necrosis factor (TNF)-alpha blockers, and serve as valuable biomarkers for treatment response in SpA. Functionally, increased Toll-like receptor triggering may be responsible for the proinflammatory response of these cells. Therefore, we propose that an exaggerated response of the innate immune system in genetically susceptible patients rather than a classic, lymphocyte-mediated autoimmune process is involved in the pathogenesis of SpA.