Anemia is a common complication of chronic kidney disease. Use of erythropoiesis-stimulating agents (ESA) has been a mainstay of treatment since 1990. A series of large trials demonstrated that ESAs have serious safety problems, including increasing cardiovascular and thrombotic events, and death. Analyses suggest high pharmacologic doses of ESAs, rather than the highly achieved hemoglobin, may mediate harm. Hypoxia-inducible factor (HIF) activators stimulate endogenous erythropoietin production and enhance iron availability. In early clinical trials, these oral agents appear to be capable of replacing ESA therapy and minimizing the need for i.v. iron therapy for chronic kidney disease–related anemia, while having other potentially advantageous actions. Large phase 3 trials are underway with several HIF activators. This commentary reviews trends in anemia management, the safety issues related to our present therapies, the role of HIF in regulating erythropoiesis, and the diverse actions of HIF activators.