Obliterative bronchiolitis (OB) is a clinical syndrome marked by progressive dyspnea and cough with the absence of parenchymal lung disease on radiographic studies. Pulmonary function testing reveals an obstructive ventilatory defect that is typically not reversed by inhaled bronchodilator. Transbronchial biopsies are insufficiently sensitive to achieve diagnosis, and in most cases, clinical, physiological, and radiological data obviate the need for the increased risk associated with open lung biopsy. This diagnosis has been documented in a variety of exposures, including fumes from flavoring plants, smoke from burn pits, and environmental sulfur gas. Among lung transplant recipients, “bronchiolitis obliterans syndrome,” a disorder with clinical and histopathological similarity to OB, represents the leading cause of long-term allograft dysfunction and mortality. After hematopoietic stem cell transplantation, chronic graft versus host disease of the lung manifests most frequently with similar clinical and pathological features. In all circumstances, immunologic and nonimmunologic mechanisms are thought to lead to airway epithelial dysfunction, which results in progressive airflow obstruction and debility. Augmentation of immunosuppression is occasionally effective in slowing or reversing the progression of disease though a significant number of patients will be nonresponders. Other immunomodulatory methods have been attempted in each circumstance where this pathology has been identified. Unfortunately, OB is poorly understood and often results in sufficient progression of disease to warrant evaluation for lung transplantation (or retransplantation). Here, we review what is known regarding pathophysiology and discuss clinical, pathological, radiological, and therapeutic factors associated with the spectrum of OB-related disease with a particular focus on lung transplantation.