The separation of benign from malignant mesothelial proliferations is an important clinical but often a difficult morphologic problem. Over the last roughly 10 years a variety of new markers that aid in this separation have been published and some older recommended markers reconsidered. Unlike previous, and largely unusable, empiric immunohistochemical (IHC) stains, these new markers, some using IHC and some using fluourescent in situ hybridization (FISH), are largely based on documented genomic abnormalities in malignant mesotheliomas. However, no marker works in all situations; rather, markers need to be chosen by the morphology of the process in question (epithelial vs. spindled) and the body cavity of interest (pleural vs. peritoneal). It is also important to be familiar with the exact pattern, for example nuclear versus cytoplasmic loss, that indicates a positive test. Furthermore, no single marker is 100% sensitive even with the optimal morphology/location, so that combinations of markers are essential. This review covers the various new markers in the literature, highlights their advantages and limitations, and suggests morphology/site specific combinations that can produce sensitivities in the 80% to 90% (and perhaps higher) range. At present only BRCA-1 related protein-1 and methylthioadenosine phosphorylase IHC, and cyclin-dependent kinase inhibitor 2A (p16) FISH have sufficient publications and reproducibility of results to be considered as established markers. 5-Hydroxymethyl cytosine, enhancer of zeste homolog 2, cyclin D1, and programmed death-ligand 1 IHC, and NF2 FISH are all potentially useful but need further study. The newly described entity of malignant mesothelioma in situ sits at the interface of benign and malignant mesothelial process; criteria for this diagnosis are reviewed.