Neutrophil migration to the site of bacterial infection is a critical step in host defense. Accordingly, blood neutrophil numbers are tightly regulated. Neutrophils are exclusively produced in the bone marrow, and their release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx in bacterial infection, its role in regulating neutrophil recruitment, granulopoiesis and neutrophil mobilization is unclear in response to lung infection-induced sepsis. Here, we used a murine model of intrapulmonary pneumococcal infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx that controls bacterial growth in lungs and dissemination and improves host survival. In addition, Cxcl1-/- mice are defective for amplification of early neutrophil precursors in granulocytic compartments and neutrophil release from the marrow. Also, CXCL1 is essential for CD62L and CD49d-dependent release of mature neutrophils from the marrow. Furthermore, administration of recombinant CXCL2 and CXCL5 after infection rescued the impairment in neutrophil-dependent host defense in Cxcl1-/- mice. Taken together, these findings identify CXCL1 as a central link among host defense, granulopoiesis and mobilization of neutrophils following bacterial pneumonia-induced sepsis