The availability of biologic agents targeting tumor necrosis factor (TNF)-alpha represents a significant advance in the management of rheumatoid arthritis. Anti-TNF-alpha therapy has been associated with dramatic improvements in the clinical signs and symptoms of rheumatoid arthritis and has been shown to greatly retard the destructive process that too often characterizes this condition. Although effective and well-tolerated in a substantial proportion of patients, primary and secondary failures of anti-TNF-alpha strategies have been well described, affecting up to one-third to one-half of subjects treated with these agents. Switching from one anti-TNF-alpha agent to a second (or even third) anti-TNF-alpha therapy has emerged as a means of addressing treatment failures with this drug class. This review examines data addressing the practice of switching anti-TNF-alpha agents in the context of initial treatment failure, with a focus on data from peer-reviewed reports.