Malignant mesothelioma is a highly aggressive tumor with poor prognosis, and new treatment paradigms are urgently needed. For testing preclinical efficacy of new therapeutic agents, establishment of appropriate animal models is crucial. We developed in vivo fluorescence imaging models for human malignant mesothelioma in mice using tumor cells engineered to express fluorescent proteins (EGFP, mRFP, mCherry, and mPlum) by lentiviral vectors. Among these fluorescent proteins, the expression of mCherry protein in the transduced tumor cells was shown to be robust and stable both in vitro and in vivo. In both, peritoneally disseminated and orthotopic pleural mesothelioma models, mCherry-positive tumors were sensitively detected and tumor growth was successfully monitored. This represents the first study to achieve sensitive tumor detection and tracking of tumor growth and development in the malignant mesothelioma mouse models by non-invasive in vivo fluorescence imaging. These imaging models can be versatile and powerful tools to explore new treatment paradigms for malignant mesothelioma.