The role of cytokines as regulators of hematopoietic stem cell (HSC) expansion remains elusive. Herein, we identify thrombopoietin (THPO) and the cytokine signaling inhibitor LNK, as opposing physiological regulators of HSC expansion. Lnk^−/− HSCs continue to expand postnatally, up to 24-fold above normal by 6 mo of age. Within the stem cell compartment, this expansion is highly selective for self-renewing long-term HSCs (LT-HSCs), which show enhanced THPO responsiveness. Lnk^−/− HSC expansion is dependent on THPO, and 12-wk-old Lnk^−/−Thpo^−/− mice have 65-fold fewer LT-HSCs than Lnk^−/− mice. Expansions of multiple myeloid, but not lymphoid, progenitors in Lnk^−/− mice also proved THPO-dependent.