Regulation of humoral immune responses is multifactorial involving appropriate activation, costimulation and the presence of specific soluble factors. Polarized type 1 or type 2 humoral responses in the laboratory mouse have been linked to expression of specific cytokines and thus can be used to provide insight into the type of response generated by infection. For example, IFN-gamma has been linked to IgG2a and IgG3 production, IL-4 to IgG1 and IgE production and TGF-beta to IgA production. Unlike the laboratory mouse, generally housed under defined conditions, highly skewed isotype expression patterns generally occur in cattle in chronic infections. A few examples of polarized responses have been noted in chronic experimental or naturally occurring infections including F. hepatica, M. paratuberculosis, C. parvum and B. abortus. In vitro studies using purified bovine B cells and various forms of costimulation and cytokines have demonstrated that isotype responses can be polarized under certain experimental conditions in vitro. That is, IgG1 expression is positively regulated by IL-4 and IgG2 expression is positively regulated by IFN-gamma. Other as yet unidentified factors may play pivotal roles in regulating humoral immune responses in large ruminant species in vivo. This possibility is best exemplified by recent studies using DNA vaccines in cattle that have been demonstrated in the mouse to be generally polarizing to a type 1 response. Surprisingly, studies in cattle using plasmid DNA as vaccination material show an almost exclusive IgG1 response. Based on a number of studies using T cell clones and various biological assays, it is clear that the classical roles of many cytokines in the laboratory mouse do not extrapolate entirely or at all to cattle. Thus, the design of adjuvants and immune modulators should be based on studies done in cattle or using bovine cells. Based on studies to date, several "holes" in the cytokine repertoire exist and these roles may be assumed by unique factors or activities of other known cytokines.