In the near future > 150 blood-doping-substances, i.e. rhEPOs, endogenously stimulated EPO, EPO-mimetics, and HIF stabilizers, as well as autologous and homologous blood transfusions, will be available for blood manipulation. rhEPO can be satisfactorily detected by isoelectic focusing, SDS PAGE analysis, and MAIIA technology. Most of the other erythropoiesis stimulating substances (ESAs) and autologous transfusions, however, can not yet be found by direct methods. The new concept is, therefore, not to detect the substance itself but the effects of the blood manipulation. Changes of an athlete's blood value over time, e.g. haemoglobin concentration or reticulocytes, are compared with the previously determined individual profile or with normal changes of these parameters obtained from an athletic reference population. Based on statistical models, e.g. Bayesian approaches the likelihood of an abnormal individual change can than be calculated. Unfortunately, most of these parameters are limited due to changes in plasma volume or to manoeuvres preceding the blood collection. A novel approach is, therefore, to control the target of all blood manipulations, i.e. the total haemoglobin mass (tHb-mass) itself. tHb-mass can accurately be determined by the CO-re-breathing method (typical error 1.4%). It is not influenced by acute exercise and only slightly affected during training periods (2-3%) which is considerably lower than the effects of blood manipulation (increase ~10-12%). In all cases, however, possible influences of altitude training (increase by ~4-6%) or illness and injury (decrease by ~2-10%) have to be considered. A change in tHb-mass by 130g (45 g) can be detected with the sensitivity (99.9%) of ~70% (~40%) until ~5 days after transfusion. Using the ratio tHb-mass / reticulocytes, the sensitivity is ~40% over a period of 4 weeks after transfusion of 45g. We, therefore, recommend the use of tHb-mass to optimize the fight against blood doping.