Only a fraction of hemophilia A patients develops a neutralizing antibody (inhibitor) response to therapeutic infusions of factor VIII (FVIII). Our present understanding of the underlying causes of the immunogenicity of this protein is limited. In the past few years, insights into the uptake and processing of FVIII by antigen presenting cells (APCs) have expanded significantly. While the mechanism of endocytosis remains unclear, current data indicate that FVIII enters APCs via its C1 domain. Its subsequent processing within endolysosomes allows for presentation of a heterogeneous collection of FVIII peptides on MHC class II, and this peptide-MHC class II complex may then be recognized by cognate effector CD4(+) T cells, leading to anti-FVIII antibody production. Here we aim to summarize recent knowledge gained on FVIII processing and presentation by APCs, as well as the diversity of the FVIII-specific T-cell repertoire in mice and men. Moreover, we discuss possible factors that can drive FVIII immunogenicity. We believe that increasing understanding of immune recognition of FVIII and the cellular mechanisms of anti-FVIII antibody production will lead to novel therapeutic approaches to prevent inhibitor formation in patients with hemophilia A. © 2012 International Society on Thrombosis and Haemostasis.