BACKGROUND The most common lung tissue samples seen by pathologists worldwide are obtained with the flexible bronchoscope. Specimens taken for examination of diffuse or multifocal parenchymal lung abnormalities pose special challenges for the general surgical pathologist, and these challenges are often compounded by high clinical expectations for accurate and specific diagnosis. OBJECTIVE To present and discuss the most common histopathologic patterns and diagnostic entities seen in transbronchial biopsy specimens in the setting of diffuse or multifocal lung disease. Specifically, acute lung injury, eosinophilic pneumonia, diffuse alveolar hemorrhage, chronic cellular infiltrates, organizing pneumonia, alveolar proteinosis, sarcoidosis, Wegener granulomatosis, intravenous drug abuse-related microangiopathy, Langerhans cell histiocytosis, and lymphangioleiomyomatosis are presented. Clinical and radiologic context is provided for the more specific diagnostic entities. METHODS The published literature and experience from a consultation practice. CONCLUSIONS The transbronchial biopsy specimen can provide valuable information for clinical management in the setting of diffuse or multifocal lung disease. Computed tomographic scans are useful for selecting appropriate patients to undergo biopsy and in limiting the differential diagnosis. Knowledge of the clinical context, radiologic distribution of abnormalities, and histopathologic patterns is essential. With this information, the surgical pathologist can substantially influence the diagnostic workup and help guide the clinician to an accurate clinical/radiologic/pathologic diagnosis.