In the 15 years since the last major NIH conference that dealt with anti-caries vaccines, we have learned much. Certainly, whole bacteria or bacterial fractions may not be proper immunogens due to the possibility of inducing tissue cross-reactivity. Our own experience (van de Rijn et al., 1976) illustrates that pitfall. But even in the era of genetically engineered vaccines, we first must understand the biological functions of our chosen immunogen before employing that pure protein in a vaccine. Our recent work (Brady et al., 1991c) indicates that antigen P1, a ubiquitous protein found on several oral streptococci, may possess different, but possibly overlapping, functional domains influencing reactions with fluid-phase salivary agglutinin (aggregation) versus fixed agglutinin (adherence). A proper vaccine would induce antibodies against the latter domain(s) thereby retarding colonization. An improper vaccine that induces antibodies against aggregation-related domains on P1 would lessen the host's ability to clear those bacteria from the oral cavity. After carefully identifying appropriate functional domains and obtaining sub-clones of the larger gene that yield truncated polypeptides typical of adherence-specific regions that are also immunogenic, we may be in a position to create the most effective vaccine. In studies employing the polymerase chain reaction (PCR) and standard cloning procedures, we have already begun to produce such polypeptides. Once a library of polypeptides is assembled, they may be tested for functional activity and for lack of induction of cross-reactivity with nonpathogenic streptococci (i.e., S. gordonii). Certain of these recombinant-specified polypeptides could serve as the basis for an anti-caries vaccine. Alternatively, peptides may be synthesized that resemble these sub-molecular regions for use in a vaccine or as competitive inhibitors of adherence but not aggregation. Clearly, a vaccine against dental caries remains a real possibility for the future.