For the clinicians with non-pathology background, first encountering the patients with pleural or peritoneal effusions, mesothelioma is only one statistically rare but clinically significant option of many differential diagnoses. This review aims to help the clinicians and broad life science audiences to understand step by step the possibilities and shortcomings of pathological diagnosing of mesothelioma, including the basic technical requirements. The first cytomorphology evaluation of pleural and peritoneal effusions in routinely stained smears enables in most cases only to identify cells suspicious for malignancy. The recent guidelines of epithelioid mesothelioma cytologic diagnosis and reporting emphasize immunochemistry (IC) in the cell blocks is mandatory whenever a diagnosis of malignancy is clinically entertained and/or cytologically suspected. The IC workup is challenging, since there is no fixed antibody panel, but multiple questions must be solved, such as 1) confirm the mesothelial or epithelial origin of isolated atypical cells and cell clusters; 2) delineate their benign or malignant nature; and 3) discriminate mesothelioma from other malignancies and metastatic disease. The rationale of the most widely clinically used IC markers is given and illustrated by the examples. The final confirmation of mesothelioma diagnosis and establishing its subtype and grade is possible only in the histological samples.