The number of antiretroviral-experienced HIV patients with multiple resistances against the currently available antiretroviral drug classes is increasing substantially. Therapeutic options for this specific group of patients are limited. The fusion inhibitor enfuvirtide represents the first new therapeutic option from a new drug class for this patient population. An optimized background therapy with remaining antiviral activity appears essential in order to avoid resistance development against enfuvirtide. Despite the high price of enfuvirtide, cost-effectiveness and increase in quality of life have been demonstrated in patients achieving virological control under optimized background and enfuvirtide therapy. In this article, the characteristics and clinical perspectives of fusion inhibitors are presented and discussed.