Immunogenicity of non-human proteins with useful therapeutic properties has prevented their development for use in the therapy of disease. However, this class of proteins could be very useful, if their immunogenicity could be markedly reduced so that many treatment cycles could be administered. One approach to reduce the immunogenicity of foreign proteins is to identify B cell epitopes on the protein and eliminate them by mutagenesis. In this article, theoretical aspects and experimental evidence for the feasibility of B cell epitope removal is reviewed. A special focus is given to our results with deimmunization of recombinant immunotoxins in which Fvs are fused to a 38kDa portion of the bacterial protein, Pseudomonas exotoxin A (PE38). Immunotoxins targeting CD22 and CD25 have produced complete remissions in many patients with drug resistant Hairy Cell Leukemia and are being evaluated in other malignancies. Experimental data summarized in this review indicates that removal of B cell epitopes is a practical approach for making less immunogenic protein therapeutics from non-human functional proteins. This approach requires grouping of the epitopes to identify targets for deimmunization followed by quantitative analysis of the decrease in affinity produced by the mutations in B cell epitopes.