Mesothelioma arises from the surface serosal cells lining the pleural, peritoneal, and pericardial cavities. It has three variants including: epithelioid, sarcomatous/desmoplastic, and biphasic types. Mesothelioma cells, predominantly of the epithelioid type, can shed into effusions as sheets, clusters/ morulae, papillae, or single cells. The challenges to cytologic diagnosis of mesothelioma are two-fold: 1. distinguishing mesothelial cells from metastatic malignant (most commonly carcinoma) cells; 2. distinguishing reactive mesothelial from mesothelioma cells. Immunocytochemistry is a helpful aid to cytologic evaluation for the former. The distinction of reactive mesothelial cells from mesothelioma can be more difficult, as there is considerable overlap in their appearances in effusion specimens. Recently developed ancillary molecular and genetic tests are proving to be useful in confirming the diagnosis of malignant mesothelioma in cytology specimens.