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Porphyromonas gingivalis is one of the primary etiologic agents of adult periodontitis and is known to produce a unique class of cysteine proteinases, termed gingipains. They consist of Arg-gingipain (Rgp) and Lys-gingipain (Kgp) and exist in the cell-associated and secreted forms. In the current review, we summarize recent knowledge on the pathophysiological role of gingipains in the virulence of P. gingivalis including host cell responses to bacterial infection and its evasion from host defense mechanisms. Studies with various P. gingivalis mutants deficient in Rgp- and/or Kgp-encoding genes and proteinase inhibitors specific for each enzyme have demonstrated that both enzymes play a substantial role in disruption of host defense mechanisms by the bacterium and its survival in vivo. Gingipains are also important in the bacterium-mediated host cell responses and the subsequent intracellular signaling in the infected cells. P. gingivalis can evade the autophagic pathway and instead directly traffic to the endocytic pathway to lysosomes in the infected cells. In addition, gingipains play an important role in acquiring resistance against destruction of the bacterium in the lysosomal system. Furthermore, a major form of the cell-associated gingipain complex composed of the catalytic domains of both enzymes, their adhesin domains, phospholipids, and lipopolysaccharide has recently been isolated and shown to contribute the bacterial evasion of host defense mechanisms and the host tissue breakdown.