This review focuses on some aspects of the complex relationship among dietary salt intake, BP, organ complication, and genetic factors. First, the reason regarding the debate in the effect of a low-salt diet on BP and organ damage is discussed. Certainly, the lack of controlled long-term studies, taken together with the opposite effect of a low-salt diet on cardiovascular risk factors, justifies the contrasting opinions about the opportunity to reduce the sodium (Na) content in the diet of the general population. Second, the contribution that the genetic polymorphisms may furnish to explain the BP response in studies that apply either a moderate or a brisk reduction of salt intake is considered. Finally, the long-term effects of diuretics that produce a decrease in body Na similar to that achieved by moderate long-term dietary salt reduction are examined. Diuretics are able to reduce organ complications in the general population. However, these beneficial effects may be the net results of opposite effects in a subset of patients. Recently, the results of an observational study on hypertensive patients who were treated with a variety of antihypertensive drugs have been published. These results show that in carriers of the 460Trp ADD1 allele (38% of the population), the administration of diuretics halves the incidence of myocardial infarction and stroke when compared with other antihypertensive treatments that produce similar reduction of BP. These data support the notion that matching of the genetic mechanism with the drug mechanisms of action produces a clear therapeutic benefit.