In this issue of Blood, Klimenkova et al demonstrate that secretory leukocyte protease inhibitor (SLPI), the natural inhibitor of neutrophil elastase (NE), plays a nonredundant role in human neutrophil differentiation. The authors show that NE itself is both required and sufficient to induce expression of SLPI in myeloid progenitors, which subsequently regulates granulocyte colony-stimulating factor receptor (G-CSFR) signaling and thereby cell proliferation, differentiation, and survival. Patients with severe congenital neutropenia (SCN) were found to have strongly reduced SLPI levels, and this article contributes to unraveling the molecular mechanism(s) underlying the block in neutrophil formation in this disease.