Genetically monomorphic bacteria contain so little sequence diversity that sequencing a few gene fragments yields little or no information. As a result, our understanding of their evolutionary patterns presents greater technical challenges than exist for genetically diverse microbes. These challenges are now being met by analyses at the genomic level for diverse types of genetic variation, the most promising of which are single nucleotide polymorphisms. Many of the most virulent bacterial pathogens are genetically monomorphic, and understanding their evolutionary and phylogeographic patterns will help our understanding of the effects of infectious disease on human history.