Malignant Pleural Mesothelioma (MPM) is a highly aggressive disease whose diagnosis could be challenging and confusing. It could occur with atypical presentations on every examined level. Here, we present three unconventional cases of the complex diagnostic process of MPM that we have experienced during routine practice: a patient with reactive mesothelial hyperplasia mimicking MPM, an unexpected presentation of MPM with persistent unilateral hydropneumothorax, a rare case of MPM in situ. Then, we review the relevant literature on each of these topics. Definitive biomarkers to confidently distinguish MPM from other pleural affections are still demanded. Patients presenting with persistent hydropneumothorax must always be investigated for MPM. MPM in situ is now a reality, and this raises questions about its management.