The tumor necrosis factor inhibitors are a diverse group of biologic agents. Although there are no studies that directly compare these agents, data from noncomparative trials suggest that all 3 agents have therapeutic activity in rheumatoid arthritis. Etanercept and infliximab have also demonstrated beneficial activity in other inflammatory arthritides (ie, psoriatic arthritis and ankylosing spondylitis [both agents] and juvenile rheumatoid arthritis [etanercept only]) and inflammatory diseases (ie, psoriasis and uveitis). Their effects in granulomatous diseases are more variable, with only infliximab demonstrating clear efficacy in the treatment of Crohn's disease, sarcoidosis, and Wegener's granulomatosis. The purpose of this brief review is to summarize current efficacy data and explore possible explanations for observed clinical differences.