The presence of high titre inhibitors makes the treatment of bleeding episodes in haemophilia patients difficult and increases the risk of uncontrollable bleeding and disability, despite optimum on-demand treatment with bypassing agents. The inability to effectively control joint bleeding leads to progressive joint disease in many patients with inhibitors. Significant mobility impairments are far more prevalent in patients with inhibitors than in those without inhibitors. Emerging data suggest that prophylaxis using bypassing agents may be effective and safe in reducing the incidence of joint bleeding during immune tolerance induction (ITI), and for patients who failed ITI or who were never candidates for ITI. Only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors. This article will review the published data on the use of bypassing agents in the prevention of bleeding, and will discuss ongoing clinical prophylaxis trials in inhibitor patients.