The development of anti-therapeutic protein immune responses in patients can be a severe complication of treatment with this class of pharmaceuticals. Antibodies generated against therapeutic proteins limit the clinical efficacy of these agents by neutralizing their biological activity and/or enhancing their clearance. An assessment of the propensity of protein therapeutics to elicit immune responses in patients is likely to become an essential part of their preclinical development. It is clear that CD4+ T-cells are an important factor in the development of long-lived, class-switched, high-affinity antitherapeutic protein antibodies. The increased risk of immunogenicity that is attributed to the presence of T-cell epitopes in therapeutic protein sequences has led to the development of a variety of methods for locating T-cell epitopes and identifying binding peptide amino acids that are important for interacting with either major histocompatibility complex class II molecules or the T-cell receptors. Manipulation of these key residues to disrupt these interactions while maintaining biological activity can result in modified therapeutic proteins with reduced immunogenicity.