This paper examines the spectrum of challenges that confront the diagnostic surgical pathologist in distinguishing benign mesothelial hyperplasia from malignant mesothelioma. The current state of the art with respect to the morphological, immunohistological, and molecular features that can assist in the evaluation of benign and malignant pleural disease is examined. Practical guidelines are offered that should reduce the risk of diagnostic error in this problematic area of surgical pathology.