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HbA1c is a trusted standard for monitoring glycemic control and predicting complications. However, there are emerging issues complicating the interpretation of HbA1c that the clinician caring for patients with diabetes needs to consider.There is increasing evidence of the potential for mismatches between HbA1c and other measures of glycemia which require some caution in HbA1c interpretation. We have attempted to characterize the nature of these discordances by developing the concept of the ‘glycation gap’ in which differences in protein glycation occurring in the intracellular space (HbA1c) versus in the extracellular space (measured as fructosamine) are compared. We have evidence that HbA1c results discordant from other measures of glycemic control may be secondary to previously unappreciated physiological variables, including erythrocyte lifespan, in hematologically normal individuals. We relate these findings to a number of HbA1c interpretation issues important for diabetes care: factors affecting hemoglobin glycation, relationship of HbA1c to glycemia, standardization of the HbA1c assay, and HbA1c relation to complications.There are an increasing number of clinical circumstances in which there are nuances to HbA1c interpretation such that standard norms for assessment of glycemic control or complication risk may need to be modified.