Protein therapeutics, such as antibodies, enzymes and toxins, are very promising reagents for the treatment of human disease. However, many therapeutic proteins are known to elicit immune responses when administered to humans. Certain antibodies work by neutralization; others reduce drug efficacy. It is clear that helper T cells are an important factor in the development of class-switched and affinity-maturated anti-therapeutic protein antibodies. Elimination of the T cell epitope seems reasonable, but it is probably impossible to remove all T cell epitopes from protein drugs because T cell epitopes are closely related to the major histocompatibility complex (MHC) molecules, which are known to be highly polymorphic. Accordingly, a possible practical approach for reducing immunogenicity involves the removal of B cell epitopes. In this case, reducing the affinity between the antigen and the B cell receptor may reduce B cell activation, even though the T cell will still be activated. Also a B cell epitope is not restricted by MHC class II molecules. This review seeks to address the identification and the characterization of B cell epitopes, and reports on the development of strategies for reducing immune response with modified B cell epitopes.