Immunogenicity is a significant problem associated with protein therapeutics, but can be predicted in advance by in silico, in vitro, and in vivo tools, which can identifiy sequences within the therapeutic protein that, when processed by T-cells, elicit an immune response. Recent developments in T-cell-dependent immunology relating to the immunogenicity of therapeutic products include the description of toll-like receptor ligands and the identification and classification of regulatory T-cells. A limitation in determining the relative immunogenicity of potential therapeutic proteins is the variance in the immunogenicity determined by in vitro or in vivo techniques in animal and human models. However, given the sophistication and high-throughput capacity of existing in silico tools and the availability of precise in vitro validation assays, accurate prediction of immunogenicity for therapeutic protein products, and more rapid translation of research discoveries into clinical success, may be within reach.