Administration of IL-2 or IL-15 in many adoptive immunotherapy regimens causes serious dose-dependent toxicities. To reduce or preclude the necessity for IL-2 use, we investigated whether genetic engineering of NK cells to express the thrombopoietin receptor (MPL) could be used as a method to improve NK cell survival and function. Here, we introduce a chimeric protein containing the extracellular, transmembrane, and membrane-proximal signaling regions of MPL fused with a membrane-distal intracellular portion of IL2RB (referred to as MPL-IL2RB). In the presence of FDA-approved specific pharmaceutical ligands eltrombopag or romiplostim, primary human NK cells retrovirally transduced to express MPL-IL2RB showed augmented cell numbers in vitro compared to NK cells expressing MPL or unmodified NK cells. When expressed in human NK cells, both MPL and MPL-IL2RB enhanced NK cell anti-tumor functions, such as lytic granule and cytokine release, and triggered appropriate signal transduction events, including STAT5 phosphorylation and mTOR activation, in response to drug ligands. Ligation of novel chimeric MPL-IL2RB co-stimulated CAR-NK cell activity in vitro and increased NK cell-mediated ADCC towards tumors in mice to levels that were higher than wild-type MPL. These data support the concept that MPL-IL2RB may be a preferred molecule to express in NK cells or T cells in a strategy to specifically augment cell proliferation and anti-tumor immunity.