Antibody-based immunotherapy may represent a realistic approach against prion diseases, given that antibodies to the cellular prion protein PrPC have been shown to antagonize deposition of the disease-associated prion protein (termed PrPSc) in in vitro assays and in laboratory animals. However, induction of protective antiprion immune responses in wild-type animals is difficult because of host tolerance to the endogenous PrPC. Several studies indicate that it might be possible to overcome tolerance to PrPC and induce immune responses to bacterially expressed, recombinant PrP. However, it is much more difficult to induce antibodies capable of recognizing native cell-surface PrPC, and there is reason to believe that the latter immune responses correlate with anti-prion protection. The difficulties involved in eliciting development of such anti-native PrPC immune responses may be partly intrinsic to B cells and, in addition, may reside in peripheral T helper tolerance.