Malignant mesothelioma (MM) is a locally aggressive tumor that originates from the mesothelial cells of the pleural and sometimes peritoneal surface. Conventional treatments for MM, consisting of chemotherapy or surgery give little survival benefit to patients, who generally die within 1 year of diagnosis. Hence, there is an urgent need for the development of alternative therapies. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MM. The closely related molecule, VEGF-C, is also implicated in malignant mesothelioma growth. VEGF-C and its cognate receptor VEGFR-3 are co-expressed in mesothelioma cell lines. A functional VEGF-C autocrine growth loop was demonstrated in mesothelioma cells by targeting VEGF-C expression and binding to VEGFR-3. The ability of novel agents that reduce the levels of VEGF and VEGF-C to inhibit mesothelioma cell growth in vitro was assessed. Antisense oligonucleotide (ODN) complementary to VEGF that inhibited VEGF and VEGF-C expression simultaneously specifically inhibited mesothelioma cell growth. Similarly, antibodies to VEGF receptor (VEGFR-2) and VEGF-C receptor (VEGFR-3) were synergistic in inhibiting mesothelioma cell growth. In addition, a diphtheria toxin-VEGF fusion protein (DT-VEGF), which is toxic to cells that express VEGF receptors was very effective in inhibiting mesothelioma cell growth in vitro. These results indicate that targeting VEGF and VEGF-C simultaneously may be an effective therapeutic approach for malignant mesothelioma. © 2003 Wiley-Liss, Inc.