Severe congenital neutropenia (CN) is a heterogeneous hematopoietic syndrome with a typical “maturation arrest” of granulocytic precursors at the promyelocytic stage, inherited in an autosomal dominant or recessive manner. Intriguingly, CN patients have the same bone marrow and blood phenotypes irrespective of inheritance. This suggests that mutations in various genes may lead to the dysregulation of the common myeloid transcription factor(s) in CN. To the extensively studied myeloid‐specific transcription factors belong CCAAT/enhancer‐binding proteins (C/EBPs) (‐α, ‐β, ‐ɛ) and PU.1. The relative levels of PU.1 and C/EBPα in granulocytic–macrophage progenitors have been suggested to regulate monocyte versus neutrophil cell‐fate choice. In CN patients, the myelopoietic maturation program is sharply shifted toward monocytopoiesis, with increased levels of monocytes and no granulocytes in the peripheral blood. We found that in myeloid cells from CN patients C/EBPα and its target gene inhibitor of DNA binding 1 (Id1) are abrogated due to a lack of lymphoid enhancer‐binding factor 1 (LEF‐1) expression but PU.1 is slightly upregulated. Based on these findings, we conclude that in LEF‐1‐deficient myeloid cells from CN patients misbalanced C/EBPα/Id1:PU.1 ratio with a strong shift toward PU.1 could play a decisive role in the improper regulation of myelopoiesis with defective granulocytopoiesis and elevated monocytic differentiation. Recently, we identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre–B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony‐stimulating factor (G‐CSF)‐triggered granulopoiesis in healthy individuals and in individuals with CN. Since CN patients respond to G‐CSF treatment even in the absence of LEF‐1 and C/EBPα, we conclude that treatment of CN patients with pharmacological doses of G‐CSF activates NAMPT/NAD⁺/SIRT1‐dependent “emergency” granulopoiesis via C/EBPß.