Glutamate acts through a variety of receptors to modulate neurotransmission and neuronal excitability. Glutamate plays a critical role in neuroplasticity as well as in nervous system dysfunctions and disorders. Hyperfunction or dysfunction of glutamatergic neurotransmission also represents a key mechanism of pain-related plastic changes in the central and peripheral nervous system. This chapter will review the classification of glutamate receptors and their role in peripheral and central nociceptive processing. Evidence from preclinical pain models and clinical studies for the therapeutic value of certain glutamate receptor ligands will be discussed.