Biologic therapies have revolutionized the treatment of rheumatic diseases in the past decade. As with any drugs, however, a variety of important safety concerns affect the choice and use of these agents. Several issues, such as the risk of infection, malignancy, or administration reactions, apply to all of these compounds, although some conditions that affect patient selection and management within these categories seem to be specific to particular biologic treatments. Other safety concerns with biologic agents, such as congestive heart failure, demyelinating disease, and hyperlipidemia, are associated with individual agents. Despite all these concerns, the therapeutic indices for biologic agents remain fairly high in relation to non-biologic DMARDs. Available safety data for all biologic agents approved for the treatment of rheumatoid arthritis are reviewed in this manuscript. With careful patient selection and appropriate vigilance on the part of treating physicians and other care providers, these compounds can be safely integrated into the therapeutic plan.