Pulmonary fibrosis (PF) is a heterogeneous clinical syndrome that represents the end-stage of chronic interstitial lung diseases. Dozens of different occupational, environmental, immune, and genetic risk factors have been associated with PF, and through the past several decades, risk factor exposures have been the driving force in the diagnostic classification of PF, thus in the current paradigm, there are dozens of different “diagnoses” of PF. Due to this emphasis on diagnostic distinction, for at least 80% of PF patients, there are no known effective treatments. We believe that radical departure from this approach is necessary in order to more rapidly develop new and better treatments for patients with PF. Our preliminary data and work from other groups suggest that while there are many risk factors for PF, patients seem to “converge” into a relatively small number of disease patterns. By understanding the molecular mechanisms that are both shared and different across these disease patterns, we will be able to develop more precise, and more effective, treatments for PF. Our hypothesis is that there is a small set of distinct, coordinated cell-type-specific gene expression changes that converge to common mechanisms driving PF. In this proposal, we will leverage recently developed genomic technologies that permit determination of gene expression profiles in individual cells (scRNA-seq) in order to (1) profile the clinical, clinical, and molecular landscape of PF lungs; (2) determine the conserved cell-type specific gene expression programs driving PF pathogenesis; and (3) define the mechanisms underlying molecular endotypes of PF. Using state-of-the-art single cell genomic technologies, innovative computational approaches, and novel organoid culture models, we will determine the gene expression programs that broadly drive the development of PF; identify novel targets for development of more precise, driver mechanism-targeted treatments; and develop a system for testing therapies at the individual patient level. By dually focusing on the mechanisms broadly at work across PF and identifying the critical molecular determinants of different forms of PF, we will rapidly accelerate progress towards better treatments for all patients with PF.