Despite improved surgical and radiotherapy techniques and the development of long-acting somatostatin analogs, some patients with acromegaly cannot attain biochemical remission. As a consequence they continue to endure debilitating symptoms and mortality remains high. Pegvisomant, a recombinant growth-hormone-receptor antagonist, suppresses production of insulin-like growth factor I. Since the introduction of this drug several years ago, long-term studies involving hundreds of patients have established efficacy of more than 85%. Raised transaminase concentrations have, however, been reported as a side effect of therapy, albeit an infrequent one. In addition, increases in tumor volume have been reported in several cases. In this Review we present the long- term data that have been gathered on pegvisomant therapy, discuss the related risks and benefits, and frame a potential therapeutic approach.