In this article, we have provided a review of the implications of diabetes and HbA1c, the standardization efforts of HbAlc as a long-term monitor of average glycemia, the pathobiology of HbA1c, as well as current measurement pitfalls associated with clinical-laboratory measurements. Long-term studies, including the DCCT and UKPDS, have established a correlation between average blood glucose (HbA1c) and the severity of diabetic complications, thereby providing clinicians and diabetic patients with established HbA1c goals to reduce these problems. This led to an increased need for standardization across all laboratories that perform HbA1c measurements. Through their significant efforts, the NGSP and IFCC have paved the way toward achieving this goal. Despite these advances, the various HbAlc methods that are currently available each have specific limitations associated with the presence of Hb variants. In areas where there is a high prevalence of Hb variants, HbA1c methods must be carefully selected to reduce the inaccuracy of these measurements. Alternative methods of determining average blood-glucose control (e.g., glycated albumin and fructosamine) are recommended in these populations in which HbA1c determinations have limited value. Unfortunately, as of yet there are no established guidelines or goals that can be followed by clinicians or diabetic patients regarding HbA1c or other glycated protein values in these populations. Importantly, clinicians should be cautious when using glycated albumin and fructosamine as an estimate of long-term average blood glucose. First, glycated albumin and fructosamine assess the degree of glycemia over a period of approximately two weeks, as opposed to two to three months, for HbA1c. Second, glycated albumin and fructosamine have not been correlated with the development of long-term complications from diabetes mellitus, as was shown with HbA1c in the DCCT or UKPDS.