Periodontitis is a disease affecting the supporting structures of the teeth. The most severe forms of the disease result in tooth loss and have recently been strongly associated with systemic diseases, including cardiovascular and lung diseases and cancer. The disease is caused by biofilms of predominantly anaerobic bacteria. A major pathogen associated with severe, adult forms of the disease is Porphyromonas gingivalis. This organism produces potent cysteine proteases known as gingipains, which have specificity for cleavage after arginine or lysine residues. The lysine-specific gingipain, Kgp, appears to be the major virulence factor of this organism and here we describe its structure and function. We also discuss the inhibitors of the enzyme produced to date and the potential pathways to newer versions of such molecules that will be required to combat periodontitis.