Parenteral vaccination is generally considered to be the most effective form of therapy for protection against infectious diseases. In recent years, vaccination at mucosal surfaces and combinatorial vaccination strategies that link immunostimulatory molecules to antigens have been developed to enhance vaccine efficacy. Prominent among immunological enhancement strategies are the bacterial A and B toxins, which include the cholera toxin (CT)A and CTB subunits. In contrast to the toxic CTA subunit, the non-toxic CTB subunit displays both carrier and immunostimulatory properties. When linked to pathogen antigens, CTB can impart immunostimulatory properties that are characteristic of the linked antigen. Vaccination strategies have also been broadened to include 'self' proteins applied for the immunological suppression of autoimmunity. When CTB is linked to an autoantigen, the outcome might be considered paradoxical. In type 1 diabetes, self proteins become strongly immunosuppressive, while cancer CTB-autoantigen fusion proteins may exert a strong inflammatory response. This review discusses the immunostimulatory and immunosuppressive roles played by the CTB subunit in vaccine protection and therapy against infectious and autoimmune diseases.