Despite the overall success of antiretroviral medications in reducing the morbidity and mortality associated with HIV infection, many patients on treatment suffer progressive disease due to intolerance or the development of resistant viral strains. Consequently, considerable research focuses on the development of new classes of antiretroviral agents with mechanisms of action different to the current classes. Enfuvirtide (T-20, pentafuside, Fuzeon™), the first drug of a new class of antiretroviral medications known as fusion inhibitors, blocks the fusion of the virus particle with the host target cell. The viral entry process begins with the attachment of viral surface glycoprotein gp120 to the host cell CD4 and chemokine receptor sites. Viral gp41 then undergoes a conformational change enabling fusion of both membranes, a critical step in the viral life cycle. Enfuvirtide is a synthetic peptide that binds to gp41, preventing the conformational change required for membrane fusion. Based on potent in vitro activity, a Phase I clinical trial of intravenous enfuvirtide was conducted that demonstrated a substantial decline in HIV plasma viral load in the highest dose group and no serious adverse effects. Phase II trials evaluated regimens of both continuous subcutaneous infusions and intermittent subcutaneous injections. Intermittent injections were pharmacokinetically superior to continuous infusions and were associated with fewer administration difficulties. For some subjects who added enfuvirtide monotherapy to an already failing regimen, the beneficial effect on viral load reduction appeared short-lived, suggesting the development of resistance. Two large randomised clinical trials comparing 'optimised background' (best available, individualised regimens based on patient history and resistance assays) versus optimised background plus enfuvirtide have recently shown a significant virological advantage (∼ 1 log10 difference from controls) at 24 weeks. In all trials to date, very few significant adverse effects have been seen - minor injection site reactions are frequent, but rarely treatment limiting. Based on these studies, enfuvirtide will likely play a significant role in the treatment of patients with limited treatment options.