Hemoglobin A1c was discovered in the late 1960s, put in the clinical practice in the 1970s and 1980s, and finally internationally standardized in the 2000s. It is still very used today, with various purposes, such as monitoring of the glycometabolic control, performing diagnosis of diabetes, evaluating the quality of life of diabetic patients, evaluating the quality of patient cares, and more. So the quality of the laboratory measurement of HbA1c has to be very high, because the laboratory professional may not know which use will be done on the single HbA1c result, and should meet the quality standards internationally defined by the IFCC. In this presentation we will define these quality standards, and we will discuss the most relevant pre-analytical factors who may impact on the measurement and interpretation of the HbA1c result. Among the various factors, particular focus will be on the presence of hemoglobin variants, and of other in vivo factors who may influence the red cell life. Among the analytical factors, the usability of some of the most diffused methodologies (HPLCs, and capillary electrophoresis techniques) will also be discussed.