The tripeptide glutathione is an important biomolecule that acts as a scavenger of free radicals and plays a role in a number of other cellular processes. A number of diseases, including Parkinson's disease, cancer, sickle cell anemia, and HIV infection, are thought to involve oxidative stress and depletion of glutathione. The heterodimeric enzyme glutamate cysteine ligase catalyzes the first, rate-limiting step in the de novo synthesis of glutathione. Functional polymorphisms within the gene encoding the subunits of glutamate cysteine ligase have the potential to affect the body's capacity to synthesize glutathione and thus, may affect those diseases in which oxidative stress and glutathione have roles. We undertook systematic screening for polymorphisms within the exons and intronic flanking sequences of the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC). We identified 11 polymorphisms in GCLC and established allele frequencies for those polymorphisms in a population fitting the demographics of the middle Tennessee area. The nonsynonymous polymorphism C1384T was found only in individuals of African descent. In addition, allele frequencies for three other polymorphisms differ between Caucasians and African-Americans. Understanding these polymorphisms may lead to better understanding of diseases where glutathione is important so that better treatments may be developed.