The first suggestion that GM-CSF may be central to PAP pathogenesis came from an unanticipated yet striking observation made by investigators originally interested in understanding the role of growth factors in hematopoiesis. Because in vitro studies6 suggested a wide variety of hematologic effects depended on GM-CSF, Dranoff and colleagues7 as well as Stanley et al8 in the same year engineered a “knockout” mouse deficient in GM-CSF (with homozygous null GM-CSF alleles; hereafter GM−/−). GM-CSF is a hematopoietic growth factor known, in vitro, to stimulate differentiation, proliferation, and survival of myeloid cells, including monocytes, macrophages, eosinophils, neutrophils, and dendritic cells.7,8 Surprisingly the genetically engineered GM−/− mice displayed a normal life span, normal bone marrow hematopoietic progenitors, and normal circulating numbers of RBCs and WBCs despite being unable to produce any GM-CSF protein. Unexpectedly, the predominant abnormality in these mice, found as early as 3 weeks of age, appeared to be lung alveolar spaces filled with granular, eosinophilic, PAS-positive material, and large, foamy macrophages—lesions highly reminiscent of PAP in humans. Thus, these results demonstrated for the first time that GM-CSF is not an essential growth factor for basal hematopoiesis but is critical for pulmonary homeostasis.