An extensive histopathological analysis of diseased tissues and organs is a crucial step in our understanding of how specific molecular and cellular events described in vitro or in animal models might by relevant to the clinical presentation of a specific disease in humans. Although in spondyloarthropathy (SpA) such an approach is hampered by the fact that some target tissues are not readily accessible for biopsy sampling (the sacroiliac joint, the axial skeleton, the enthesis, and the eye), numerous histological studies of the synovial membrane of the peripheral joint, the gut, and the skin have contributed to new insights into the cellular and molecular base of SpA. Firstly, the peripheral synovitis is characterized by an extensive hypervascularity and the presence of specific macrophage and T cell subsets. Secondly, the fact that the same subsets of macrophages and T cells can be identified in the gut mucosa, even before histological inflammation is present, point to a role for early immune alterations of the gut in the development of the disease. Thirdly, macrophages and macrophage-derived cytokines such as the pro-inflammatory TNFalpha and the anti-inflammatory IL-10 appear to be crucial mediators of the tissue inflammation. Therefore, neovascularization, recirculation of inflammatory cells between gut and synovium, and macrophage-derived cytokines are all potential targets for immunotherapy. As a proof of concept, anti-TNFalpha treatment has been demonstrated to have an impressive clinical effect as well as a major impact on the histological tissue inflammation. Further research should benefit from the combination of classical histopathology with newer molecular techniques (genomics, proteomics) to unravel the molecular and cellular base of the different disease presentations and should aim to translate these basic findings into clinical applications such as histopathological differential diagnosis and follow-up of targeted therapies.