Background: Immunohistochemistry is crucial for the proper diagnosis of malignant mesothelioma, especially in cases with complex morphology and in biopsy and cytology specimens where it is difficult or impossible to determine the tumor architecture. In the vast majority of instances, the correct identification of tumor lineage is made possible by the application of a tailored panel of mesothelial- and epithelial-specific markers. Methods: The authors review the most commonly used cytologic preparations, fixatives, and antibodies used in effusion ICC. Results: Through the utilization of cell block preparations and a panel of antibodies appropriate for the differential diagnosis in question, ICC conditions utilized in surgical pathology can be most closely replicated. Conclusions: Accurate differentiation between malignant mesothelioma and lung adenocarcinoma in pleural effusion cytology is still a big challenge. Therefore, it is mandatory to search for new diagnostic immunohistochemical markers.