During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells biologics have provided more specific therapeutic interventions with less immunosuppression. Clinical use, however, has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.