The management of malignancies in humans constitutes a major challenge for contemporary medicine. Despite progress in chemotherapy, bone marrow transplantation, surgical measures, and radiation technologies, and in immunological and immunomodulatory approaches, humans continue to succumb to cancer due to tumor recurrence and metastatic disease. The excitatory neurotransmitter glutamate, which regulates proliferation and migration of neuronal progenitors and immature neurons during the development of the mammalian nervous system, is present in peripheral cancers. Since both neuronal progenitors and tumor cells possess propensity to proliferate and to migrate, and since glutamate and glutamate receptors are known to modify these phenomena in the nervous system, we proceeded to investigate the possible influence of glutamate antagonists on the proliferation and migration of tumor cells. We found and recently reported that glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonists inhibit the proliferation of human colon adenocarcinoma, astrocytoma, breast and lung carcinoma, and neuroblastoma cells in vitro. The antiproliferative effect of glutamate antagonists is Ca(2+)-dependent and results from decreased cell division and increased cell death. Glutamate antagonists produce morphological alterations in tumor cells, which consist of reduced membrane ruffling and pseudopodial protrusions, and decrease their motility and invasive growth. Furthermore, glutamate antagonists enhance in vitro cytostatic and cytotoxic effects of common chemotherapeutic agents used in cancer therapy. These findings demonstrate the anticancer potential of glutamate antagonists and suggest that they may be used as an adjunctive measure in the treatment of cancer.