The IgG responses to a variety of allergens are predominated by IgG1 and IgG4 antibodies. With several allergens, the IgG1 response appears to precede the IgG4 response and this switch may be driven by repeated allergen exposure. It remains to be determined whether there is any causal relationship between subclass restriction and the regulation of specific IgE. The question of whether IgG4 antibodies are protective or pathological is still unresolved. Human models are needed to further analyze the interrelationships between T cells, cytokines and B cell isotype expression. The antibody response to allergens appears to be an ideal experimental system for studying antigen-specific isotype regulation in humans. The subclass patterns are remarkably reproducible between individuals, and allergic and normal human subjects, who have been immunized naturally or therapeutically, are readily available as a source of cells. Isolation of allergen-specific T cells that putatively regulate subclass expression would seem to be a worthwhile endeavor. Understanding the molecular and cellular events that initiate and control isotype expression will play an important role in the rational design of immunogens and therapeutics, aimed at optimizing protective immunity and diminishing the pathological effects of autoimmune and allergic responses.