Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.0001), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases. Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and irreversible interstitial pneumonia, with symptoms including progressive cough, shortness of breath, and ultimately respiratory failure, with a median survival of only 3-5 years post diagnosis 1. The disease is believed to be caused by a dysregulated wound healing response to various epithelial injuries leading to fibrosis of the lung interstitium 1. Two medications (nintedanib 2 and pirfenidone 3) are effective treatments for IPF; though neither can reverse the disease 4. Thus, lung transplantation is currently the only option for a cure 5 , even though this procedure has the highest failure rate of all organ transplantation options (54% at 5 years 6). Better understanding of mechanisms underpinning progression of pulmonary fibrosis could lead to improved outcomes via identification of new therapeutic targets. To add to the complexity surrounding IPF, disease progression is also heterogeneous, with some individual patients experiencing long-term stability and others rapid loss of lung function. A number of longitudinal cohort studies have been created with the goal of better characterizing IPF pathobiology using proteomic measurements 7-10. These efforts have identified individual proteins, including blood MMP-7 11,12 , CCL18 13 , and blood surfactant protein D 14,15 , as potential prognostic biomarkers. However, it has been difficult to replicate these findings across multiple cohorts 16,17 , especially when attempting to validate specific, prognostically-relevant cutoff concentrati...