A review of cytogenetic and molecular genetic findings in human malignant mesotheliomas (MMs) is presented. The complex profile of somatic genetic changes characteristic of MMs implicates a multistep process of tumorigenesis in this malignancy. In particular, the occurrence of multiple, recurrent cytogenetic deletions in MMs suggests that loss and/or inactivation of tumor suppressor genes (TSGs) are critical to the development and progression of such tumors. Karyotypic and comparative genomic hybridization analyses of MMs have demonstrated frequent deletions of specific regions within chromosome arms 1p, 3p, 6q, 9p, 15q and 22q, and subsequent loss of heterozygosity (LOH) studies have documented high frequencies of allelic loss from each of these chromosomal sites. Positional candidate gene approaches have identified TSGs within two of these regions, i.e., p16/CDKN2A at 9p21 and NF2 at 22q12, which are frequently altered in MMs. Homozygous deletions appear to be the major mechanism affecting p16/CDKN2A, whereas inactivating mutations coupled with allelic loss occur at the NF2 locus. High density LOH analyses have pinpointed minimal regions of deletion in 1p, 3p, 6q, and 15q and are expected to facilitate efforts to identify putative TSGs at these locations which contribute to the pathogenesis of MMs.