Glutamate, the major excitatory neurotransmitter in the central nervous system (CNS), is essential for numerous brain functions including learning and memory, yet excess glutamate released after acute CNS injury or during chronic disease causes massive cell death in gray and white matter. Its physiological and pathological effects are mediated by ionotropic [N-methyl-D-aspartate (NMDA), AMPA, and kainate (KA) receptors] and G-protein-coupled metabotropic glutamate receptors. AMPA receptors (AMPAR) are essential for basal excitatory synaptic transmission and forms of synaptic plasticity thought necessary for learning and memory, play a pivotal role in spinal cord pain transmission and neuronal plasticity accompanying pain sensitization, so AMPAR antagonists possess potential as therapeutic drugs for neurological disorders (e.g., epilepsy, schizophrenia, pain). Additionally, overstimulation of AMPARs can induce Ca2+ overload leading to cell damage and death, relevant for acute and chronic neurodegenerative pathologies such as cerebral ischemia, amyotrophic lateral sclerosis, and Parkinson's disease, making AMPA receptor subtypes potential targets for therapeutic intervention. The present Perspective deals with drugs acting as AMPA receptor inhibitors, cites evidence for their therapeutic effectiveness in clinical trials, and discusses proposed mechanisms of action and implications for current understanding of the biomolecular basis of these pathologies.