Given the emphasis of recent clinical trials on targeting high hemoglobin levels, critical knowledge gaps remain, most notably the absence of information on lower hemoglobin targets (<125 g/L). The largest randomized, placebo-controlled outcome study to explore this range was the 1990 Canadian Erythropoietin Study Group (CESG) trial (5), which included 118 patients and lasted only 6 months. The placebo group in the CESG trial had a mean hemoglobin concentration of 74 g/L (SD, 12), compared with 2 treatment groups that achieved mean hemoglobin levels of 102 g/L (SD, 10) and 117 g/L (SD, 17), respectively, by using 50% to 60% less epoetin than the normalization group in the Normal Hematocrit Trial. In the CESG trial, substantial benefits to quality of life and physical performance were associated with the 2 higher hemoglobin targets, although outcome measures did not differ between the 2 treatment groups. Subsequent larger clinical trials have not shown clinically meaningful sustained improvements in quality of life, although hemoglobin levels for the control groups in these studies were similar to those in the treatment groups of the CESG trial (10, 14–15, 18). A second knowledge gap is the lack of data to facilitate individualization of therapies. Higher-functioning persons are probably more aware of the symptoms of anemia than more sedentary persons, thereby deriving greater benefit from higher hemoglobin targets (20). In this context, it is ironic that the major clinical trials focused on participants with prevalent cardiovascular disease or diabetes. A third gap, pertaining to the use of iron and other anemia-management agents, is the lack of data on concurrent administration of multiple anemia therapies.