Neutrophil specific granule deficiency (SGD) is a rare congenital disorder. The neutrophils of these patients display atypical bilobed nuclei; lack expression of at least one primary and all secondary and tertiary granule proteins; and possess defects in chemotaxis, disaggregation, receptor upregulation, and bactericidal activity. SGD patients suffer frequent and severe bacterial infections. Although the first of five patients worldwide was reported in the early 1970s, the molecular basis for the defect was discovered only recently. This review presents data implicating the functional loss of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBPε) as a causative agent in the development of SGD. The murine model for SGD provides evidence for defects in eosinophil granule gene expression and indicates abnormalities in macrophage maturation and function. Deficiencies in multiple myeloid lineages, in addition to neutrophils, indicate the importance of C/EBPε in regulating important innate immune and inflammatory responses critical for host defense.