Impaired erythropoiesis causes anemia during genetic disorders, chronic disease, and infection. In studies of the underlying mechanisms researchers have increasingly focused on gamma interferon (IFN-gamma). Here, we identified a previously unrecognized role for interleukin-15 (IL-15) in red blood cell homeostasis and demonstrated that IFN-gamma and signal transducer and activator of transcription protein 1-dependent pathways up-regulate expression of IL-15 in vivo. These findings identified new therapeutic targets for anemia.