Mutations in the cathepsin C gene (CTSC) have been identified as causal for the Papillon-Lefèvre syndrome (PLS), which includes prepubertal periodontitis (PP). Some CTSC mutations are causal for PP without PLS. No relationship has been demonstrated between CTSC mutations and other forms of periodontitis. Genetic polymorphisms in a candidate gene approach have been explored as risk factors for periodontitis. There is limited evidence that some polymorphisms in the genes encoding interleukins (IL)-1, Fc gamma receptors (Fc gammaR), IL-10 and the vitamin D receptor, may be associated with periodontitis in certain ethnic groups. However relatively large variations in carriage rates of the Rare (R)-alleles among studies on any polymorphism were observed. The available studies appear under-powered and do not adequately take into account other pertinent risk factors for periodontitis. Future studies should include larger cohorts, should clearly define phenotypes and should adequately control for other risk factors. In addition to the candidate gene approach, alternative strategies need to be considered to elucidate the gene variations, which confer risk for periodontitis.