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The hepatitis C virus (HCV) epidemic represents a significant unmet medical need. Current treatment is arduous and less than 50% effective. Indeed, interferon-alpha treatment is so unpleasant that asymptomatic patients will often stop treatment. Heartened by the success of HIV protease inhibitors, researchers have considered inhibition of the HCV NS3 serine protease an attractive mode of intervention. This account discusses the structure and function of NS3 4A and the prospects of its success as a therapeutic target. The review includes a detailed discussion of the role of the NS4A co-factor, requirements for inhibition and some recent examples of peptidomimetic and small-molecule inhibitors.