Spondyloarthropathies are a cluster of interrelated and overlapping chronic inflammatory rheumatic diseases that primarily include ankylosing spondylitis, reactive arthritis, and the arthritis associated with psoriasis and inflammatory bowel diseases. The primary pathologic sites are the entheses (the sites of bony insertion of ligaments and tendons); the axial skeleton, including the sacroiliac joints; the limb joints; and some nonarticular structures, such as the gut, skin, eye, and aortic valve. Although spondyloarthropathies are not associated with rheumatoid factor, they show a strong association with HLA-B27; however, this association varies markedly among various spondyloarthropathies and among ethnic groups. The most widely used classification criterion, from the European Spondyloarthropathy Study Group, encompasses the currently recognized wider disease spectrum, with a sensitivity and specificity that generally exceed 85%. Spondyloarthropathies occur in genetically predisposed persons and are triggered by environmental factors, but the cellular and molecular mechanisms of inflammation are not yet fully understood. Chlamydial and many enterobacterial infections can trigger reactive arthritis, but an infectious trigger for ankylosing spondylitis has not yet been established. HLA-B27 itself is involved in enhancing genetic susceptibility, but the underlying molecular basis is still unknown; additional genes include the putative susceptibility genes for Crohn disease, ulcerative colitis, and psoriasis. A specific susceptibility gene for Crohn disease, NOD2, is located on chromosome 16q12, and one of the candidate genes for psoriasis, PSORS1, has been mapped to a 60-kb fragment on chromosome 6p, which is telomeric to the HLA-C locus. This paper reviews the efficacy of anti-tumor necrosis factor-alpha therapy and other therapeutic advances.