The interpretation of diagnostic tests for the detection of subgingival bacterial species is dependent on knowledge of the microbial etiology of destructive periodontal diseases. Specific etiologic agents of these diseases have been sought for over 100 years; however, the complexity of the microbiota, an incomplete understanding of the biology of periodontal diseases, and technical problems have handicapped this search. Nonetheless, a number of possible pathogens have been suggested on the basis of their association with disease, animal pathogenicity, and virulence factors. The immunological response of the host to a species and the relation of successful therapy to the elimination of the species have also been used to support or refute suspected periodontal pathogens. Current data suggest that pathogens are necessary but not sufficient for disease activity to occur. Factors which influence activity include susceptibility of the individual host and the presence of interacting bacterial species which facilitate or impede disease progression. Recent studies have attempted to distinguish virulent and avirulent clonal types of suspected pathogenic species and seek transmission of genetic elements needed for pathogenic species to cause disease. Finally, the local environment of the periodontal pocket may be important in the regulation of expression of virulence factors by pathogenic species. Thus, in order that disease result from a pathogen, 1) it must be a virulent clonal type; 2) it must possess the chromosomal and extra-chromosomal genetic factors to initiate disease; 3) the host must be susceptible to this pathogen; 4) the pathogen must be in numbers sufficient to exceed the threshold for that host; 5) it must be located at the right place; 6) other bacterial species must foster, or at least not inhibit, the process; and 7) the local environment must be one which is conducive to the expression of the species' virulence properties.