Many mechanical and systemic conditions can cause joint pain and synovitis. When rheumatologic illness is suspected, the initial evaluation begins with an accurate history, physical examination, and selective use of confirmatory testing, which can help avoid common pitfalls inherent in serologic evaluation. Tests for erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies and lupus anticoagulant, HLA-B27, uric acid level, and Lyme disease, either alone or in combination, may support certain diagnoses. Using these tests nonselectively may yield false-positive results, causing unnecessary concern and expense. However, using these tests effectively may reduce the number of unneeded invasive procedures.