The major histocompatibility complex (MHC) of cattle is known as the bovine leukocyte antigen (BoLA) and is located on chromosome 23. BoLA has been linked to variation in resistance to disease including bovine leukemia virus‐induced lymphoma and mastitis. Moreover, BoLA appears to influence other traits such as milk yield, growth and reproduction, which are not often measured in humans, and variations in individual immune response to antigen. The BoLA appears to be organized in a similar way to the MHC region in humans, but there are notable differences. A major rearrangement within the class II region has led to the division of the BoLA into two distinct subregions of chromosome 23 separated by about a third of the chromosome’s length. The class IIa subregion contains functionally expressed DR and DQ genes, while the class IIb subregion contains the genes of undefined status such as DYA, DYB, DMA, DMB, DOB, DOA, TAP1, TAP2, LAP2 and LMP7. In addition, one pair of human class II genes (DP) does not appear to have an equivalent in cattle, and there is one pair of DY genes that seem to be found only cattle, sheep and goats. In humans, three classical, polymorphic class I genes (HLA‐A, ‐B and ‐C ) are each present on all haplotypes. However, in cattle, none of the four (or more) classical class‐I genes identified are consistently expressed, and haplotypes differ from one to another in both the gene number and composition. These variations in both class I and II are likely to play an important role in cattle immune responses. This review summarizes current knowledge of the structural and functional features and disease association of BoLA genes.