It is well accepted that pathogens can evade recognition and elimination by the host immune system by varying their antigenic targets. Thus, it has become a truism that host immunity is a major driver and determinant of the antigenic diversity of pathogens. However, it remains puzzling how host immunity selects for antigenic diversity at the level of the pathogen population, given that hosts have acquired immune responses to multiple antigens of most pathogens - sometimes through multiple effectors of both humoral and cellular immunity. In this Opinion article, we address this puzzle and the related question of why pathogens often have diversity at multiple antigenic loci. Here, we describe five hypotheses to explain the polymorphism of multiple antigens in a single pathogen species and highlight research relevant to our current models of thinking about multi-locus antigenic diversity.