Pleural biopsies for the evaluation of malignant mesothelioma can be some of the most challenging cases faced by the practicing surgical pathologist. We review the epidemiology, clinical presentation, and imaging studies in patients with malignant mesothelioma, and then present a practical approach to the diagnosis using the cytologic features for malignancy and whether there is an epithelioid or spindled morphology; four main scenarios are discussed. The pertinent immunohistochemical work-up is reviewed for each scenario. Following this general overview, more unusual histologic patterns are compared and unusual presentations are discussed. Brief mention of grading systems for malignant mesothelioma and the use of electron microscopy and molecular studies is made. Practical considerations in the diagnosis of malignant mesothelioma are made throughout.