Ankylosing spondylitis (AS) is the most common type of spondylarthropathy seen in clinical practice. Several reports have appeared in the past 2 years that have significantly advanced our understanding of the pathogenesis and treatment of this disease. Two recent studies finally provide direct experimental data in support of the hypothesis that a key trigger for disease is the intracellular proteolysis of bacterial and self-proteins producing peptides that exhibit molecular mimicry, thereby leading to activation of cross-reactive T cells once these peptides are presented on the cell surface. Two additional studies have shown that once disease is established, tumor necrosis factor alpha (TNF ) is a pivotal cytokine from the perspective of therapeutic intervention. One study provides evidence in support of the use of bisphosphonates for the treatment of AS. The association between HLA–B27 and ankylosing spondylitis is among the strongest of any HLA antigen to human disease, although the pathogenetic mechanism(s) remains unknown. The importance of bacteria has also been highlighted by the presence of intestinal mucosal inflammation in up to 60% of patients, and the observation that intestinal bacteria are essential to the development of arthritis in B27 transgenic rats (1,2). One currently favored hypothesis proposes that disease follows induction of cytotoxic T cell autoreactivity in the course of T cell-mediated defense to certain bacteria following presentation by B27 of an arthritogenic self-peptide(s), perhaps derived from joint/entheseal cartilage, in a process that could involve cross-reactivity with bacterial-derived peptides (3). However, until recently, evidence in support of this hypothesis has been circumstantial and largely based on epidemiologic evidence of differing B27 subtype associations with disease. A major advance in our understanding of the pathogenesis of AS has been the recognition that inflammation within subchondral bone marrow is an early and consistent feature of the pathology of AS at both axial and peripheral sites (4). In addition, osteoporosis is an important feature of AS with an increased cumulative risk for vertebral fracture that is related to disease activity (5,6). This may be evident within the first few years of disease. For the past several decades, the management of this disorder has been largely restricted to the use of nonsteroidal antiinflammatory drugs (NSAIDs) and physical modalities, with little attention being paid to the increased bone resorption evident from the outset of disease. Limited controlled data also supported the use of sulfasalazine in AS patients with peripheral synovitis (7,8). Nevertheless, clinical improvement with these agents is modest. Bisphosphonates have enjoyed widespread use in the treatment of a variety of disorders of bone metabolism, but it is less widely known that they may also suppress macrophage function, particularly at the high concentrations achieved at sites of high bone turnover typically associated with subchondral marrow inflammation as may be seen in AS (9). TNF has proven to be a pivotal cytokine from the perspective of therapeutic intervention in rheumatoid arthritis and the finding of TNF in the serum, synovium, and sacroiliac joints of AS patients (10) raised hopes that targeting TNF might also be beneficial in the treatment of AS.