Successful treatment of tumors remains one of the greatest challenges in oncology. The recognition that different stem cell types can integrate appropriately throughout the mammalian brain following transplantation has unveiled new possibilities for their use in neural transplantation. Our laboratory has shown that both human mesenchymal and neural stem cell types home to sites of cerebral pathology and thus can be armed with therapeutic transgenes, a strategy that can be used to inhibit tumor growth by targeting angiogenesis or selectively induce apoptosis in proliferating tumor cells in the brain. Using our recently established malignant, invasive and resection models of highly malignant human brain tumors that mimic clinical settings and synthetic extracellular matrix (sECM) encapsulated therapeutic stem cells, we show that secreted therapeutic proteins are continuously delivered by encapsulated stem cells, target both the primary and the invasive tumor deposits and have profound anti-tumor effects. Our studies demonstrate the efficacy of encapsulated therapeutic stem cells in clinically relevant mouse tumor models and will have implications for developing effective cancer therapies. These studies demonstrate the strength of employing engineered stem cells and real time imaging of multiple events in preclinical-therapeutic tumor models and form the basis for developing novel cell based therapies for cancer.