Severe primary graft dysfunction affects 15–20% of lung transplant recipients and carries a high mortality risk. In addition to known donor, recipient, and perioperative clinical risk factors, numerous biologic factors are thought to contribute to primary graft dysfunction. Our current understanding of the pathogenesis of lung injury and primary graft dysfunction emphasizes multiple pathways leading to lung endothelial and epithelial injury. Protein biomarkers specific to these pathways can be measured in the plasma, bronchoalveolar lavage fluid, and lung tissue. Clarification of the pathophysiology and timing of primary graft dysfunction could illuminate predictors of dysfunction, allowing for better risk stratification, earlier identification of susceptible recipients, and development of targeted therapies. Here, we review much of what has been learned about the association of protein biomarkers with primary graft dysfunction and evaluate this association at different measurement time points.