Dental caries is an infectious, transmissible disease caused by certain bacterial species colonizing the oral cavity. Dental caries continues to pose a major health threat to a significant number of individuals, particularly individuals of lower economic and minority status. With the advent of national care for all citizens, measures directed at prevention rather than treatment are eagerly sought as health dollars become tightly stretched. The notion that children at risk for developing dental caries can be identified prior to onset of disease based on predictors from early childhood, or even better, from predictors present in the mother, constitutes a scientifically and sociologically viable approach to health care. Before such measures can be adopted, however, the natural history of dental caries must first be understood. Examination of the current and past literature reveals the presence of no more than half a dozen longitudinal studies specifically designed to ascertain the development of the cariogenic biota in infants and its association with future caries outcome. Indeed, the association of dental caries with the mutans streptococci based on prospective longitudinal observations remains tenuous. We feel strongly that a carefully controlled, longitudinal study of the acquisition of the cariogenic bacteria and other members of the oral biota constitutes a sound approach toward understanding the natural history of this disease. Here, we blend together the traditional bacteriological cultivation methods with the newer genetic technologies to answer the question as to when and from where the indigenous oral bacteria arise in infants. Mindful that caries is a multifactorial disease, particular attention will be paid to the possible interactions between bacterial species as well as the temporal aspects of acquisition. For example, pre-colonization of tooth surfaces by S. sanguis or A. viscosus may modulate the colonization of the mutans streptococci. The source of cariogenic bacteria and the fidelity in which it is transmitted may also influence caries outcome. The tools needed to answer our queries about how and from where oral bacteria are acquired are not available with better methods in the near horizon. The arbitrary primer- polymerase chain reaction (AP-PCR) method for fingerprinting strains of bacteria will greatly enhance our ability to study transmission. We believe the windows concept of bacterial colonization, if substantiate by this study, will present researchers the opportunity to manipulate the colonization patterns as well as develop strategies for introducing genetically altered, virulent strains into the oral cavity of the infant deemed at risk based upon newly discovered risk factors. The knowledge that mothers constitute the principal source of indigenous bacteria to her infant and time in which it is transferred to her infant opens up the possibility of isolating MS from the mother, genetically altering its cariogenic properties, and then re-introducing back into the mother and allowing her to naturally transmit the attenuated strain to her infant. Vaccination of infants at risk must be predicted on the understanding of the normal indigenous biota and its relationship to disease. These and other viable concepts can only arise from a foundation in which natural history studies form the cornerstone.