In recent years, a growing number of biologic agents have become available for the treatment of various autoimmune, neoplastic, cardiovascular, infectious, allergic, and other conditions. Their introduction has resulted in marked clinical improvements for many patients. Nevertheless, a variety of adverse reactions have been observed with these agents. Because many biologic agents affect key components of sundry physiologic processes, a number of important adverse reactions might be considered mechanism based. Other adverse reactions relate to the agent rather than the target, including hypersensitivity reactions. As a means of exploring the spectrum of potential adverse effects related to biologic agents and their mechanisms, this review will focus on the experience to date with biologic agents used for the treatment of autoimmune disorders. An understanding of the spectrum and types of reactions possible with biologic agents, as well as the mechanisms underlying such reactions, will help clinicians use them optimally.