Management of anemia in chronic kidney disease (CKD) and dialysis patients with erythropoiesis stimulating agents continues to be an area of debate. Recent US Food and Drug Administration documents indicate that Normal Hematocrit Study (NHS) completed in 1996 had more patients (1,265 vs. 1,233) and showed significantly increased deaths or myocardial infarctions (p = 0.01; risk ratio: 1.28; 95% CI: 1.06-1.56) rather than the indeterminate evidence of harm (risk ratio: 1.30; 95% CI: 0.9-1.9) reported in the 1998 publication. This review places the NHS study results in context with the other three major anemia trials, which, together, contain approximately 70% of all patients reported in trials using active therapy in both arms and examining a hemoglobin target >12 g/dl in CKD and dialysis. The potential impact of the ongoing TREAT trial, with its unique design characteristics, is also reviewed. This review outlines the known risks and benefits of various anemia targets based on these completed trials to better inform physicians about the realistic goals from anemia treatment.