While an understanding of the structure and function of a generically described immune system is essential in contemporary biomedicine, it is clear that a one-size-fits-all approach applied across multiple species is fraught with contradictions and inconsistencies. Nevertheless, the breakthroughs achieved in immunology following the application of observations in murine systems to that of man have been pivotal in the advancement of biology and human medicine. However, as additional species have been used to further address biologic and safety assessment questions relative to the structure and function of the immune system, it has become clear that there are differences across species, gender, age and strain that must be considered. The meaningfulness of these differences must be determined on a case-by-case basis. This review article attempts to collect, consolidate and discuss some of these species differences thereby aiding in the accurate placement of new observations in a proper immunobiological and immunopathological perspective.