The functional significance of polymorphism among MHC class II promoters in man and mouse is here reviewed, mainly in terms of the hypothesis of differential expression. The hypothesis proposes that differences between antigen-presenting cells in MHC class II expression exert a co-dominant effect on the Th1 - Th2 cytokine balance, such that class II molecules of one type come to control to a greater extent the production of one group of cytokines, and those of another type the production of the alternative group. The survey deals with the influence of signal strength and antigen-presenting cell type on T-cell subset differentiation; functional differences between MHC class n molecules not obviously related to determinant selection; disease protection mediated by HLA alleles; mechanisms possibly responsible for allotypic and isotypic bias; overdominance (heterozygous advantage) in selection for expression of class II alleles; MHC class II promoter structure and function; inter-locus and inter-allele variability within human MHC class II gene upstream regulatory regions; a comparison of these polymorphisms in mouse and man; read-out of class II promoter function; and a comparison with expression of MHC class I. We conclude that the evidence that this variation is functionally active (i.e. controls expression) is increasing, but is not yet compelling. The crucial test still to come, we suggest, is whether or not the biological effects attributable to this polymorphism will line up with molecular studies on expression.