The practice of medicine requires that the assimilation of today's best available data be directed toward individual patient-care decisions. In the absence of definitive data, surrogate measures are adopted to anticipate how therapeutic strategies would influence clinical outcomes and prognosis. Unfortunately, randomized controlled clinical trials (RCTs) have not always found these estimates of outcome to be reliable. Anemia is a clear marker of adverse prognosis, which can be modified by erythropoietic stimulating proteins (ESP). At present, there is sufficient uncertainty regarding the risks and benefits of ESP treatment in patients with chronic kidney disease and anemia to warrant major RCTs. This article reviews the rationale and design features for these trials.