Cytologic examination of the body cavity fluid is very important because the specimens represent a significant percentage of nongynecologic samples and this cytologic examination may be the first, best or only chance for making the diagnosis of an underlying malignancy. The purposes of body cavity fluid examination are to correctly identify cancer cells and if possible, to identify the tumor types and primary sites when presented with unknown primary tumor sites. The most important basic differential diagnosis is that of benign and reactive disease vs malignant disease. Reactive mesothelial cells are a consistent population in body cavity fluid, and these are the most versatile cells in the body. Due to the specific environment of the body cavity, the exfoliated reactive mesothelial cells may show significant morphologic overlap with the morphology of cancer cells. With a focus on the differential points between reactive mesothelial cells and metastatic adenocarcinoma cells, the practical diagnostic approaches, the diagnostic clues and the pitfalls to achieve a correct diagnosis are presented in this review.