The existence of discrete populations of throat and skin strains of group A streptococci has long been recognized; however, a molecular basis for this distinction is not known. The emm gene structure was analyzed for 105 isolates obtained from patients with well-defined group A streptococcal diseases: uncomplicated pharyngitis, impetigo, and acute rheumatic fever. Four emm gene subfamily forms, defined by nucleotide sequence differences in regions encoding the peptidoglycanspanning domain of M and M-like surface proteins, were found to exist in five different chromosomal patterns among naturally occurring isolates. Strong correlations were made between disease and the number and arrangement of emm subfamily genes. These findings provide a genetic basis for the historical references to “throat,” “skin,” and “rheumatogenic” types.