The primary ecological niche for group A streptococci (GAS) is the superficial epithelium of the human throat and skin, wherein the organism can reproduce, cause a localized infection (pharyngitis or impetigo), and readily transmit to new hosts. Distinct “throat” and “skin” strains, as defined by M-serotype, are widely recognized. Yet, core housekeeping genes point to widespread genetic exchange between strains of the GAS population. A central question of interest: What is the molecular basis for tissue site preferences for infection among GAS? Genes giving rise to M- and T-serotypes are likely to provide important clues. A meta-analysis of 29 population-based surveys, involving >5,000 pharyngitis and impetigo isolates of known emm type, shows that throat and skin specialist strains are distinguished by their emm genes/products, including functional domains that bind fibrinogen and plasminogen, respectively. The emm pattern-defined throat specialists dominate GAS harboring the FCT-1 pilus region encoding T-serotype (71%), whereas 86% of GAS with FCT-3 are skin specialists, and 80% with FCT-4 are generalists. Phylogenies of the pilus adhesin (Cpa) and backbone (FctA) subunits (FCT-3/FCT-4 regions) reveal 10 and 16 sequence clusters, respectively. Extensive genetic recombination is evidenced via 44 unique Cpa-FctA cluster combinations among GAS of 88 emm types. Despite ample genetic mixing, the association between plasminogen-binding emm cluster D4 and certain Cpa clusters is highly non-random (p = 0.0001), as expected for genes conferring key adaptive traits. Mapping of serological typing genes onto a clinical-ecological framework can lead to the generation of well-supported hypotheses that can be experimentally tested.