Background: Diabetes mellitus is a major health problem worldwide with long-term micro- and macrovascular complications responsible for a majority of its morbidity and mortality. The development and progression of these complications relate strongly to glycemic control. Methods: We reviewed the literature extensively for studies that relate glycemic control to the development and progression of diabetic complications. We discuss the problems of standardizing glycohemoglobin measurements for monitoring diabetic therapy and also consider recently developed electrospray ionization mass spectrometry methods that have been considered as candidate reference methods for estimation of glycohemoglobin. Results: Several clinical trials and studies have clearly shown that improved glycemic control is strongly associated with decreased development and/or progression of complications in both type 1 and type 2 diabetes mellitus. Irrespective of the methods used for estimating glycohemoglobin, these results underline the importance of glycohemoglobin for guiding therapy of diabetes mellitus. Recently developed candidate reference methods promise to yield greatly improved standardization for the measurement of glycohemoglobin. Conclusions: Glycohemoglobin measurement remains the optimal indicator of glycemic control in diabetic patients, but translation of findings from clinical trials to clinical practice worldwide demands consistent values across all assays. To ensure that the important prognostic information still applies to all diabetic patients with the application of the reference method(s), the hemoglobin A1c values reported in the major clinical trials will have to be translated into statistically and computationally compatible values based on the new reference system(s).