Tumor necrosis factor (TNF)-alpha antagonists are promising therapeutic agents for patients with severe autoimmune and rheumatologic conditions. Unfortunately, their use has been associated with an increased rate of tuberculosis, endemic mycoses, and intracellular bacterial infections. Infliximab, 1 of 3 available drugs in this novel class, appears to be associated with the greatest risk of infection, likely because of its long half-life and induction of monocyte apoptosis. Prospective trials are necessary to determine the exact risk associated with these agents, particularly the newer TNF-alpha antagonists. More specific TNF-alpha blockers, which reduce inflammation while maintaining adequate immunity, are needed. In the meantime, a thorough work-up is mandatory for all febrile illness occurring in TNF-alpha blocker recipients. We present 4 patients who developed severe infections during TNF-alpha antagonist therapy, review the literature, and discuss current guidelines for surveillance and prophylaxis.