Chronic obstructive pulmonary disease (COPD) is a health problem of utmost global significance affecting tens of millions of people and it is resistant to current therapies. COPD is hallmarked by an irreversible and progressive deterioration in lung function, which is caused by destruction of lung parenchyma due to inflammation, and fibrosis in small airways. Most COPD is caused by irritants (smoke) and one near universal feature of COPD is a heightened chronic inflammatory response in lung involving macrophages, epithelial cells, granulocytes, dendritic cells and lymphocytes. Lung injury caused by cigarette smoke and irritants strongly induces the release of many inflammatory mediators including myeloid colony-stimulating factors (CSFs). CSFs link development of granulocytes and macrophages from the bone marrow with tissue inflammation, autoimmunity and host defence, and while GM-CSF is highly implicated in COPD pathogenesis, the role of G-CSF is much less well understood. The SH2 domain-containing inositol 5’ phosphatase SHIP-1 is a negative regulator of myeloid cell proliferation and growth-factor mediated survival, exemplified in mice where deletion of SHIP-1 causes neutrophil and myeloid cell hyperplasia, myeloid cell accumulation in the spleen, lymph nodes and lungs, and the development of emphysema and spontaneous lung fibrosis that resembles human COPD. G-CSF levels are significantly elevated in the serum and bronchoalveolar lavage fluid of SHIP-1-deficient mice and the mice exhibit dramatically increased numbers of myeloid progenitors in spleen. We now show that deletion of G-CSF from SHIP-1-deficient mice leads to their increased survival, and the mice exhibit markedly reduced lung disease, loss of splenomegaly and lymphadenopathy phenotypes, and dramatic diminution of extramedullary hematopoiesis. Collectively, our findings show that G-CSF plays a crucial role in mobilizing hematopoietic stem cells from the bone marrow and inciting tissue inflammation in SHIP-deficient mice, which plays an important role in the development of chronic inflammatory lung disease.