Mesothelin, a glycosylphosphatidylinositol (GPI) anchored cell surface protein, is a potential target for antibody-based cancer therapy due to its high expression in mesothelioma, ovarian cancer, pancreatic cancer, cholangiocarcinoma and other cancers. The SS1P immunotoxin and MORAb-009 (amatuximab), a chimeric monoclonal antibody, are currently being evaluated in clinical trials. In this review, we discuss the role of mesothelin in cancer progression and provide new insights into mesothelin-targeted cancer therapy. Recent studies highlight three mechanisms by which mesothelin plays a role in cancer progression. First, mesothelin may aid in the peritoneal implantation and metastasis of tumors through its interaction with mucin MUC16 (also known as CA125). Second, mesothelin may promote cancer cell survival and proliferation via the NF-κB signaling pathway. Finally, mesothelin expression promotes resistance to certain chemotherapy drugs such as TNF-α, paclitaxel, and a combination of platinum and cyclophosphamide. However, its cancerspecific expression makes mesothelin a potential target for monoclonal antibody therapy. New human monoclonal antibodies targeting mesothelin have been isolated by phage display technology and may provide opportunities for novel cancer therapy.