The major pneumococcal virulence determinant is its capsule, and pneumococcal epidemiology is based on 91 capsular serotypes, each corresponding to the structure of the capsular polysaccharide determined by the type-specific capsular genome. Here, we provide the beginnings of an approach to intertwine serotype epidemiology, capsular regulatory gene characteristics on the basis of existing sequence information, and the reanalysis of published epidemiological data. We present an approach to explain epidemiological characteristics of serotypes on the basis of genetic differences in their capsular regulatory genes. The part of the capsular genome that regulates capsular expression falls into 2 highly divergent sequence clans: the ancestral pneumococcal capsular regulatory gene sequences (present in 49 serotypes) and laterally transferred sequences (present in 32 serotypes). Our survey of epidemiological data showed a tendency of the ancestral type of the capsular regulatory genome to be associated with carriage and the laterally transferred sequences to be associated with invasive disease isolates. The regulatory gene region shows mosaic structures that have signatures of recent recombination events, reminiscent of structures known from antibiotic resistance genes.