Malignant pleural mesothelioma (MPM) is the most frequent pleural neoplasm, with asbestos exposure as one of the recognized carcinogen agents, causative in 80% of cases. The prognosis is poor; median survival of untreated cases is 6-9 months, with fewer than 5% of patients surviving 5 years. Sarcomatoid mesothelioma (SM) represents the subtype with the worst outcome and median survival ranging from 3.5 to 8 months. In the last few years, an accurate differentiation between the subtypes of MPM has become a crucial issue, due to differences in chemosensitivity and clinical outcome, and several studies have evaluated different immunohistochemical markers to better define the diagnosis. The different and worse outcome of patients with SM and, in general, nonepithelioid subtypes makes it intriguing to select these cases to better study the biomolecular profile in order to find factors linked to prognosis and/or predictive of therapeutic response. Considering recent studies on miRNA and genetic mapping, further investigation of this rare subtype might represent a field for basic and clinical-translational research providing for more tailored therapies.