Periodontitis is a chronic inflammatory disease of the supporting structures of the teeth caused by a polymicrobial infection and, despite the general improvement of oral health status and advances in treatment; it continues to afflict a large percentage of adults worldwide. If morbidity caused by tooth loss due to advanced periodontitis was not enough, mounting evidence suggests a causative link between periodontal and cardiovascular diseases. It is now generally accepted that a relatively small consortium of anaerobic Gram-negative bacteria (P. gingivalis, T. denticola and T. forsythia) described as the “red complex” is strongly associated with the pathological changes in the periodontium. Each of these bacteria is well equipped with virulence factors among which, proteolytic enzymes are the best studied. In the case of P. gingivalis, gingipains were shown to significantly contribute to bacterial virulence in vivo. Proteolytic activity produced by P. intermedia may also add to the destructive potential of the red complex consortium since the presence of this bacterium strongly correlates with the presence of P. gingivalis and T. forsythia in the subgingival communities. We hypothesize that different proteases affect host defense system at different non-redundant sites and these concerted multiple assaults should lead to a significantly greater effect than the additive action of individual proteases. Therefore, we postulate that this kind of interaction occurs in the periodontal pocket and may be experimentally verified using specific mice models of periodontal disease using monomicrobial and synergistic mixed microbial infections with a combination of P. gingivalis and P. intermedia wild-type and protease-deficient mutants. Our proposed hypothesis of combined proteolytic periodontopathogen activity may have significant potential importance for the treatment and prevention of periodontal disease in the future.