Natural killer (NK) cells are classified as members of the type 1 innate lymphoid cells (1). NK cells defend against infection, both directly and by orchestrating T cell, DC, monocyte, and macrophages (Mφ) responses (2). NK cells also may eliminate cancer cells and senescent cells (3, 4). Peripheral NK cells develop in the bone marrow and secondary lymphoid organs, where they are nurtured by multiple cell types and cytokines. IL-15, which is critical for mature NK cell development, homeostasis and function (5), signals via a trimeric receptor comprised of IL-15Rα, CD122, and CD132. IL-15 RNA is made in the bone marrow, secondary lymphoid tissues, and many nonlymphoid tissues, including skeletal muscle and adipose tissue. Although IL-15Rα is part of the IL-15 receptor, it also is required for IL-15 secretion and appearance on cell surfaces. In Mφ, DC, and other producing cells, IL-15 and IL-15Rα bind together with very high affinity. The complex is transported to the cell surface, where it stimulates neighboring NK cells in a paracrine fashion (5, 6). IL-15/IL-15Rα complexes also circulate to act on NK cells in an endocrine fashion (7). Two observations indicate that physiological IL-15 levels are dose-limiting for NK cells homeostasis: hemizygous IL-15 mice have low NK cell number and exogenous IL-15 boosts NK cell number in both normal mice and primates (8–10).