In 1985, we reported that a naturally occurring human antibody (anti-Gal), produced as the most abundant antibody (1% of immunoglobulins) throughout the life of all individuals, recognizes a carbohydrate epitope Galalpha1-3Galbeta1-4GlcNAc-R (the alpha-gal epitope). Since that time, an extensive literature has developed on discoveries related to the alpha-gal epitope and the anti-Gal antibody, including the barrier they form in xenotransplantation and their reciprocity in mammalian evolution. This review covers these topics and new avenues of clinical importance related to this unique antigen/antibody system (alpha-gal epitope/anti-Gal) in improving the efficacy of viral vaccines and in immunotherapy against cancer.