This Review focuses on the emergence of mycobacterial disease in patients undergoing treatment for rheumatic disease with four new drug classes-tumor necrosis factor (TNF) inhibitors, human interleukin (IL)-1 receptor antagonists, anti-CD20 antibodies and CD4+ T-cell costimulation modulators-collectively referred to as biologic agents. Mycobacterial disease is a major cause of severe infection in patients undergoing anti-TNF therapy. Reports are now emerging of an association between mycobacterial infection and antirheumatic treatment with anti-IL-1 or anti-CD20 antibodies. Although tuberculosis is the most common mycobacterial disease, nontuberculous mycobacterial (NTM) disease is an increasingly recognized problem in this setting. Among the antirheumatic drugs currently in development, agents that target IL-17, IL-23, Janus kinase-signal transducers and activators of transcription signaling, and metalloproteinases are likely to confer an increased risk of mycobacterial disease. Although screening and preventive treatments have lowered the incidence of active tuberculosis, these tools are not applicable to patients with NTM disease. All patients receiving drugs associated with an increased risk of mycobacterial disease should be carefully monitored, and suspect lesions should undergo Mycobacterium culture. Further studies are needed to determine the prevalence of NTM disease in this setting, and to evaluate the safety of simultaneous anti-TNF and antimycobacterial treatment.