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Ovarian tumors are difficult to treat, and more than half of patients with high-grade serous ovarian carcinoma (HGSOC) die within 5 years. Three quarters of these tumors overexpress mesothelin. Anderson et al. find that human T cells that express an engineered T-cell receptor specific for mesothelin can kill multiple HGSOC cell lines. To study the effectiveness of mesothelin-specific engineered T cells in vivo, a mouse model was evaluated for resemblance to human HGSOC. The mouse peritoneal-cavity metastatic tumors have a transcriptome profile similar to human metastatic tumors, including upregulation of multiple inhibitory pathways present in HGSOC. Mouse mesothelin-specific T cells recognize and kill ovarian cancer cells in vitro and accumulate in the tumors, and co-infusion with a mesothelin peptide vaccine promotes expansion and increases T-cell persistence. The presence of active tumor-specific engineered T cells correlates with tumor killing and prolonged mouse survival. This model is useful for testing immunologic interventions for patients with HGSOC and already serves as the basis for a clinical trial. Read more starting on page 1412. Original fluorescence micrograph of the ovarian tumor microenvironment provided by the Greenberg laboratory. Artwork by Lewis Long.