The formation of antibodies against factor VIII or factor IX that inhibit replacement therapy is currently the most serious treatment-related complication faced by patients with haemophilia. This review highlights non-modifiable and modifiable risk factors that determine the development of these antibodies. The non-modifiable risk factors include patient genotype for haemophilia, immunogenotype, ethnicity and positive family history. Age, intensity of treatment and the type of clotting factor administered are identified as modifiable risk factors. These risk factors are likely to be identified more accurately in forthcoming prospective randomized controlled trials and current patient registries. Through a more complete picture of a patient's overall risk profile, individually tailored treatment schedules might be developed that could minimize the incidence of inhibitor formation and thus maximize therapeutic benefit.