Fibrosis is a pathobiological process common to many human diseases characterized by the progressive replacement of normal parenchymal tissue with collagen-rich extracellular matrix (Desmoulière et al., 2003). Fibrogenesis occurs through the aberrant accumulation and activation of myofibroblasts, which deposit extracellular matrix components and remodel the tissue (Kuhn and McDonald, 1991; Zhang et al., 1994), culminating in increased tissue mechanical stiffness (Gross and Hunninghake, 2001; Tomasek et al., 2002). In its most severe clinical manifestations, fibrosis can reach a progressive and self-sustaining phase, the cause of which remains largely mysterious. Much attention has focused on the role that soluble inflammatory and fibrogenic mediators play in the initiation and progression of fibrosis (Wynn, 2008). However, recent observations have highlighted the fact that variations in matrix stiffness potently alter fibroblast morphology, proliferation, TGF-ß signaling, and myofibroblast activation (Arora et al., 1999; Wang et al., 2000; Paszek et al., 2005; Goffin et al., 2006; Wipff et al., 2007). These findings raise the intriguing possibility that stiffening of the mechanical environment, long regarded only as an outcome of fibrosis, might play a pivotal role in driving the cellular behaviors that promote, amplify, and perpetuate fibrosis. In the rat liver, macroscale measurements of organ stiffness during onset of carbon tetrachloride–induced fibrosis indicate that stiffening occurs rapidly and may even precede measurable fibrosis, suggesting a possible role for stiffening in the initial stages of fibrosis (Georges et al., 2007). In the lung, fibrotic lesions are heterogeneously distributed, and although it is known that fibrosis alters gross tissue mechanics (Bachofen and Scherrer, 1967), measurements of stiffness at the local microscale relevant to resident cells are not available. Thus, the role of matrix stiffening in promoting lung fibrogenesis remains untested. To assess the role that pathophysiological matrix stiffening plays in the promotion of fibrogenesis, we designed experiments to measure the stiffness of normal and fibrotic lung tissue