α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPA receptors or AMPARs) are involved in fast excitatory neurotransmission and as such control multiple important physiological processes. AMPARs also are involved in the dynamics of synaptic plasticity in the nervous system where they impact neuroplastic responses such as long-term facilitation and long-term potentiation that regulate biological functions ranging from breathing to cognition. AMPARs also regulate neurotrophic factors that are strategically involved in neural plastic changes in the nervous system. As with other major ionotropic receptors, modulation of AMPARs can have prominent effects on biological systems that can include marked tolerability issues. AMPAR potentiators (AMPAkines) are positive allosteric modulators of AMPARs which have therapeutic potential. Medicinal chemistry combined with new pharmacological findings have defined AMPAkines with favorable oral bioavailability and pharmacological safety parameters that enable clinical advancement of their therapeutic utility. AMPAkines are being investigated in patients with diverse neurological and psychiatric disorders including spinal cord injury (breathing and bladder function), cognition, attention-deficit-hyperactivity disorder, and major depressive disorder. The present discussion of this class of compounds focuses on their general value as therapeutics through their impact on synaptic plasticity.