Disease is a major source of economic loss to the livestock industry. Understanding the role of genetic factors in immune responsiveness and disease resistance should provide new approaches to the control of disease through development of safe synthetic subunit vaccines and breeding for disease resistance. The major histocompatibility complex (MHC) has been an important candidate locus for immune responsiveness studies. However, it is clear that other loci play an important role. Identifying these and quantifying the relative importance of MHC and non-MHC genes should result in new insights into host-pathogen interactions, and information that can be exploited by vaccine designers. The rapidly increasing information available about the bovine genome and the identification of polymorphisms in immune-related genes will offer potential candidates that control immune responses to vaccines. The bovine MHC, BoLA, encodes two distinct isotypes of class II molecules, DR and DQ, and in about half the common haplotypes the DQ genes are duplicated and expressed. DQ molecules are composed of two polymorphic chains whereas DR consists of one polymorphic and one non-polymorphic chain. Although, it is clear that MHC polymorphism is related to immune responsiveness, it is less clear how different allelic and locus products influence the outcome of an immune response in terms of generating protective immunity in outbred animals. A peptide derived from foot-and-mouth disease virus (FMDV) was used as a probe for BoLA class II function. Both DR and DQ are involved in antigen presentation. In an analysis of T-cell clones specific for the peptide, distinct biases to particular restriction elements were observed. In addition inter-haplotype pairings of DQA and DQB molecules produced functional molecules, which greatly increases the numbers of possible restriction elements, compared with the number of genes, particularly in cattle with duplicated DQ genes. In a vaccine trial with several peptides derived from FMDV, BoLA class II DRB3 polymorphisms were correlated with both protection and non-protection. Although variation in immune responsiveness to the FMDV peptide between different individuals is partly explainable by BoLA class II alleles, other genetic factors play an important role. In a quantitative trait locus project, employing a second-generation cross between Charolais and Holstein cattle, significant sire and breed effects were also observed in T-cell, cytokine and antibody responses to the FMDV peptide. These results suggest that both MHC and non-MHC genes play a role in regulating bovine immune traits of relevance to vaccine design. Identifying these genes and quantifying their relative contributions is the subject of further studies.