The treatment of juvenile idiopathic arthritis (JIA) has been revolutionized by the use of novel biologic agents that have much improved patients' short-term and, according to early evidence, long-term outcomes. Currently available biologic agents used to treat patients with JIA include tumor necrosis factor (TNF) blockers, various agents that target interleukin (IL)-1 and the IL-6 receptor, T-cell co-stimulation inhibitors and antibodies to B-lymphocyte antigen CD20. These agents are increasingly used early in the course of the disease (often in combination with other immunosuppressive medications) and often for long periods of time, as patients can be difficult to wean from their use. Safety concerns (especially the long-term effects of biologic therapy) are, therefore, being examined more closely. For instance, in 2009, the FDA issued a warning related to the development of malignancies in patients with JIA who had used anti-TNF medications for >2.5 years. In this Review, data related to the safety profile of all currently available biologic agents used to treat JIA are examined, with a particular focus on anti-TNF therapy, the most studied biologic agent for JIA. Safety issues that need further study, including the implementation of registries to monitor long-term drug safety, are also discussed.