In patients with heart failure, anemia is highly prevalent and associated with impaired outcomes. These clinical observations necessitate the realization of pharmacologic interventions to mitigate the effects of anemia and a number of available agents are being tested in large, randomized clinical trials. However, from the pathophysiologic point of view, anemia is multifactorial and difficult to attribute to a single mechanism. Moreover, classic indicators for the identification of etiology and pathways have been found to be less accurate than expected. For these reasons future clinical trials must be designed to be able to elucidate the complexity of mechanisms and the implications for treatment strategies.