Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and binds to a variety of receptors, which recently have also been detected in peripheral, non-excitable cells. New research suggests that this abundant amino acid might also be involved in the growth of tumor cells acting via novel receptor-mediated autocrine/paracrine signal transduction pathways. We report here that glutamate, as well as glutamate receptor reactive drugs, differentially modulate growth and morphology of human histiocytic lymphoma-derived U937 cells. These effects were different depending on the culture milieu: in glutamine-free medium the glutamate receptor agonists, kainate (KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), but also the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), significantly decreased the proliferation of U937 cells. In contrast, in cultures devoid of glutamate, glutamine and serum, the agonists significantly increased cell proliferation whereas the antagonist CNQX showed no effect. These data point to a significant role of peripheral glutamate receptors in tumor cell proliferation.