Differentiation of mesothelioma from bronchogenic carcinoma is necessary to determine the optimal treatment strategy, and often requires histologic and/or histochemical examination of tissue samples collected by tumor biopsy. Mesothelioma can be primarily sarcomatoid or epithelial, and the epithelial type histology resembles that of bronchogenic adenocarcinoma. Acid mucopolysaccharide-positive, perinuclear keratin-positive, and CEA/Leu-M1-negative samples favor diagnosis of mesothelioma over adenocarcinoma. Clinical and radiologic presentation as well as gross appearance of the different tumor types can be markedly similar. While smoking history has a different impact on the risk for development of mesothelioma versus bronchogenic carcinoma, it is not helpful in distinguishing the two entities clinically.