Idiopathic pulmonary fibrosis (IPF), diffuse, patchy irreversible fibrosis of the lung parenchyma, with unknown etiology—a very practical way to describe a deadly disease about which we know very little and can offer very little for therapeutic intervention. The natural history of IPF is unknown, and most conclusions drawn about pathogenesis have evolved from studies of biopsy material from established disease. These “snapshots” of disease activity have been used to implicate inflammation as the major pathogenic mechanism because we see patchy areas of interstitial inflammation, evidence of progressive injury, and tissue remodeling and fibroblastic foci, with dense deposits of collagen and honeycomb changes, now collectively termed “usual interstitial pneumonia”(1–3). However, these terms describe the morphology there now, not how it developed. It is likened to asking someone who had been held incommunicado for the past 6 months to decipher what happened to the World Trade Towers using only a “snapshot” of Ground Zero as it is today. This is hardly a case for much conviction in current conclusions about the pathogenesis of IPF. Animal models of pulmonary fibrosis have been studied, but they are, by default, of known etiology, and the only real similarity is that they display fibrogenesis. Nonetheless, for the past 30 odd years, we have approached this disorder by assuming that it is a chronic inflammatory disease, and therapy must therefore attack the inflammatory pathways that propagate the progressive nature of the disorder (3). Alas, this has taken us nowhere, with the most potent of antiinflammatory drugs yielding little or no effect in IPF (2, 4)(to the point that some clinicians commonly use response and/or nonresponse to corticosteroid treatment as a differential diagnosis from other lung inflammatory fibrotic diseases). How, then, can we be so sure of the involvement of inflammation in the pathogenesis of the disease? In fact, when one examines the accumulated human evidence in detail (2) and looks to other experimental data and models of fibrogenesis for clues to pathogenesis, it is just as easy to conclude that the inflammation we see in biopsy material is paraphenomena, associated with a more direct tissue-based defect in cell injury, communication, and repair (5, 6). Instead of inflammation driving the fibrogenic process with chronicity an aspect of repeated episodes of injury, I would argue that after an initial insult or injury, the normal physiologic response of inflammation leads to matrix stimulation with proliferation and altered phenotype of mesenchymal cells (fibrogenesis) to stop the injury and provide temporary repair. This is usually followed by matrix mobilization (fibrolysis) and apoptosis of repair cells, both mesenchymal and inflammatory, and return to normal organ function. In the case of IPF, this normal process is diverted, with retention of altered mesenchymal cell phenotype (fibroblasts and myofibroblasts) through avoidance of apoptosis, with continued matrix production and reduced matrix mobilization. In addition, the altered stromal cell population and activated epithelium release a series of profibrogenic factors, such as transforming growth factor-ß and platelet-derived growth factor, which interact with the deposited matrix at the site of abnormal repair (7), thus creating a new microenvironment in patchy areas of the lung. Other areas remain in normal structure and environment. The ability of matrix to sequester many growth and differentiation factors to create a “fibrogenic” microenvironment is well established (7, 8). Many of these factors act on inflammatory cells in normal passage through the tissue modulating susceptibility …