Many epidemiological evidences have proven the association between smoking and periodontal disease. The causality can be further established by linking findings of traditional epidemiological studies with the developments in molecular techniques that occurred in the last decade. The present article reviews recent studies that address the effect of smoking on molecular and genetic factors in periodontal disease. Most findings support the fact that tobacco smoking modulates destruction of the periodontium through different pathways: microcirculatory and host immune systems, connective tissue, and bone metabolism. Although smokers experience an increased burden of inflammatory responses to microbial challenges compared to non-smokers, understanding the association between smoking and periodontal diseases involves substantial problems with respect to accuracy of measurements, and particularly, sampling of many subjects. It remains unclear whether genetic susceptibility to periodontal disease is influenced by exposure to smoking or the effect of smoking on periodontal disease is influenced by genetic susceptibility. Employment of molecular techniques may play a key role in further elucidation of mechanisms linking smoking and periodontal destruction, the direct relationship as environmental factors and indirect relationship through genetic factors.