A variety of opportunistic pathogens have been reported to infect patients receiving tumor necrosis factor (TNF) antagonists for the treatment of autoimmune diseases. These pathogens are numerous, and include coccidioides, histoplasma, nontuberculous mycobacteria, Mycobacteria tuberculosis, and others of public health concern. Accordingly, TNF antagonists should be used with caution in patients at risk for tuberculosis, and screening for latent tuberculosis infection should be undertaken before anti-TNF therapy is initiated. Although screening and prevention efforts have decreased the risk of tuberculosis in this setting, optimal screening methods represent an area of evolving controversy. This article discusses the latest developments in screening methodologies for latent tuberculosis infection, as well as potential preventive and therapeutic considerations for opportunistic infections associated with anti-TNF agents and other biologic therapies.