The most important adaptive responses from a physiological stance involved the cardiovascular system, consisting in particular of elevation of the cardiac output and its redistribution to favor the coronary and cerebral circulations, at the expense of the splanchnic vascular beds. The evidence regarding these physiological responses, especially in experimental studies that permit the control of many variables, is particularly powerful and convincing. On the other hand, there is a remarkable lack, in quality and quantity, of clinical studies addressing how normal physiological adaptive responses may be affected by a variety of diseases and conditions that often accompany and may complicate anemia, and interactions with other such compounding variables as age and different patient populations. For these reasons, it is not possible to offer guidelines on how to increase, maintain, or even to determine optimal DO2 in high-risk patients and how best transfusion strategies might be used under these conditions. From the brief review of physiological principles and the strong consensus in the literature, it is evident that cardiac function must be a central consideration in decisions regarding transfusion in anemia, because of the critical role it plays in assuring adequate oxygen supply of all vital tissues. Particular attention should be paid to the possible presence of CAD or incipient or cardiac failure, as these conditions may require careful transfusions to improve DO2 at levels that may not necessitate such interventions when cardiac disease is absent. Although the cerebral circulation also serves an obligate aerobic organ unable to tolerate significant hypoxia, there is little convincing evidence to support the notion that cerebral ischemia is aggravated by anemia and that this can be prevented by improved DO2 through rapid correction of anemia. Consequently, the arguments favoring transfusions in the presence of ischemic heart disease do not appear to apply to occlusive cerebrovascular disease. Because firm evidence is lacking on the interactions of concurrent diseases and anemia in various patient populations, understanding of the physiological consequences of anemia, and of the diseases concerned, is useful but not fully sufficient to provide firm and rational guidance to transfusion practice in specific complex clinical instances. A good deal of clinical and experimental investigation is required to support fully rational and comprehensive guidelines. In the meantime, prudent and conservative management, based on awareness of risks and sound understanding of the normal and pathological physiology, must remain the guiding principle.