Tumor necrosis factor-alpha (TNF-alpha) inhibitors are increasingly becoming the standard of care for treating a number of inflammatory diseases. However, treatment with TNF-alpha inhibitors carries an inherent risk of compromising the immune system, resulting in an increased susceptibility to infections and malignancies. This increased risk of infection is of particular concern in Asia, Eastern Europe, and Latin America where tuberculosis (TB) and viral hepatitis are endemic. In this brief review, we examine the literature and review the impact of TNF-alpha inhibitors on the incidence and the reactivation of latent disease with respect to TB, hepatitis C infection, and hepatitis B infection. Our findings show that TNF-alpha inhibitors are generally safe, if used with caution. Patients should be screened prior to the initiation of TNF-alpha inhibitor treatment and given prophylactic treatment if needed. In addition, patients should be monitored during treatment with TNF-alpha inhibitors and after treatment has stopped to ensure that infections, if detected, are treated promptly and effectively. Our analysis is consistent with other reports and guidelines.