Historically, myeloperoxidase activity and subsequent production of hypochlorous acid has been associated with the killing of host-invading microorganisms (bacteria, viruses, and fungi). Currently, there is a wealth of evidence that the MPO polymorphism and enzyme activity is associated with a wide range of pathological and biological processes, including lung cancer carcinogenesis. Although the molecular epidemiology reports reviewed in this chapter are not in complete agreement on all aspects of their findings, it is evident that the MPO polymorphism contributes to the modulation of overall lung cancer risk. Four of the five molecular epidemiologic studies reviewed in this chapter utilized similar case-control study designs with quite different sources of populations. These studies all demonstrate that the MPO variant genotype modulates overall lung cancer risk. However, these studies are not in agreement regarding age and gender effects, and gene-environmental interactions. The nested case control study designed utilized by Misra et al. (35) is a valid and sound approach, but their results found no evidence of an association. Certainly, heterogeneity in study populations can contribute to the variability between these studies. Additionally, epidemiologic issues such as case-control matching and sources of control populations may contribute to the conflicting findings. Thus, the publication of inconsistent or null studies as well as other positive findings is certainly encouraged to elucidate the range of effects associated with the MPO polymorphism and lung cancer risk.