Polymorphic N-acetyl transferases (NAT) 1 and 2 are involved in detoxification of xenobiotic arylamines and hydralazines. These common environmental chemicals may be related to the pathogenesis of many spontaneous disorders, mainly malignancies, but also disimmune or degenerative diseases, for which a polygenic predisposition has been suggested. Hence, polymorphic NAT genes (NAT2 has been the most studied one) may be low-penetrance risk genes for some of these disorders. Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinsons, Alzheimers, Behcets and periodontal diseases , as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. Future research should be based on well-designed studies, with adequate sample sizes and homogeneous recruitment criteria, to obviate the proliferation of small studies that are time- and resource-consuming without offering definite answers.