Development of alloantibodies against infused factor VIII (FVIII) is the most significant complication of haemophilia care today. Antibodies inactivate the procoagulant activity of FVIII and inhibit patients' response to replacement therapy. As inhibitors tend to develop early in the course of FVIII treatment, the challenge is to bring patients through the critical early phase of FVIII exposure without inhibitor development as the subsequent risk is much lower. Disease severity, major FVIII gene defects, family history and non-Caucasian race are major risk factors for inhibitor development. Other variables thought to play a role in inhibitor formation include age at first treatment, intensity of early treatment, use of prophylaxis and product choice [especially recombinant vs. plasma-derived von Willebrand factor (VWF)-containing concentrates]. As these treatment-related variables are modifiable, they provide opportunity to minimize inhibitor incidence at the clinical level. At present, most data regarding inhibitor development derive from retrospective studies, registry reviews, small case series and uncontrolled studies. Findings have often been conflicting, which precludes drawing definitive conclusions. Nevertheless, some clarity is beginning to emerge. Intensity of early treatment appears to be a stronger risk factor for inhibitor development than timing of first treatment. Controlled early antigen presentation via prophylaxis looks promising, particularly in conjunction with strategies to avoid immunological danger signals, but the timing of introduction and optimal regimen are not yet known. Several reports suggest that plasma-derived VWF-containing FVIII concentrates are less immunogenic than recombinant or VWF-free plasma-derived concentrates, but this is awaiting confirmation in the ongoing prospective Survey of Inhibitors in Plasma-Product Exposed Toddlers study.