In recent years a vast amount of data has been published on the association between the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin-converting enzyme and renal disease. It has become clear that the polymorphism does not affect the prevalence of renal disease. However, data on the association with progression of renal disease and therapy response are still contradictory. Moreover, sufficient data on the physiological significance of this polymorphism are still lacking. This contribution provides an overview of the available studies and the potential pitfalls in interpreting the data. We also discuss the putative mechanisms for the association between the DD genotype and progression of renal disease and suggest directions for the future that might be employed to further clarify the role in renal pathophysiology.