A considerable amount of continuous proliferation and differentiation is required to produce daily a billion new neutrophils in an adult human. Of the few cytokines and factors known to control neutrophil production, G-CSF is the guardian of granulopoiesis. G-CSF/CSF3R signaling involves the recruitment of non-receptor protein tyrosine kinases and their dependent signaling pathways of serine/threonine kinases, tyrosine phosphatases, and lipid second messengers. These pathways converge to activate the families of STAT and C/EBP transcription factors. CSF3R mutations are associated with human disorders of neutrophil production, including severe congenital neutropenia, neutrophilia, and myeloid malignancies. More than three decades after their identification, cloning, and characterization of G-CSF and G-CSF receptor, fundamental questions remain about their physiology.