The discovery of nitric oxide (NO) and carbon monoxide (CO) as biological messengers in the brain has significantly advanced our understanding of synaptic transmission. NO, a labile free-radical gas, is synthesized by nitric oxide synthase (NOS) from L-arginine and diffuses from nerve terminals. Unlike conventional neurotransmitters, NO forms covalent linkages with targets such as guanylyl cyclase (GC) and other proteins, rather than interacting reversibly with receptors. NO plays multiple roles, including cytotoxicity in activated macrophages, vasodilation, and neuromodulation in the nervous system. NOS enzymes are activated by calcium and calmodulin and can be constitutive or inducible, depending on the stimulus. Inducible NOS is particularly important in inflammation and tissue damage. Neuronal NOS is localized to specific neuronal populations and influences neurotransmitter release, long-term potentiation (LTP), and autonomic functions. However, excessive NO production can lead to neurotoxicity, particularly in conditions like focal ischemia and neurodegenerative diseases. CO, produced by heme oxygenase, also functions as a neurotransmitter candidate. CO is involved in maintaining endogenous cGMP levels, mediating glutamate action at metabotropic receptors, and regulating chemosensory responses in the carotid body. Both NO and CO have expanded our understanding of synaptic transmission and the mechanisms underlying neuronal function.The discovery of nitric oxide (NO) and carbon monoxide (CO) as biological messengers in the brain has significantly advanced our understanding of synaptic transmission. NO, a labile free-radical gas, is synthesized by nitric oxide synthase (NOS) from L-arginine and diffuses from nerve terminals. Unlike conventional neurotransmitters, NO forms covalent linkages with targets such as guanylyl cyclase (GC) and other proteins, rather than interacting reversibly with receptors. NO plays multiple roles, including cytotoxicity in activated macrophages, vasodilation, and neuromodulation in the nervous system. NOS enzymes are activated by calcium and calmodulin and can be constitutive or inducible, depending on the stimulus. Inducible NOS is particularly important in inflammation and tissue damage. Neuronal NOS is localized to specific neuronal populations and influences neurotransmitter release, long-term potentiation (LTP), and autonomic functions. However, excessive NO production can lead to neurotoxicity, particularly in conditions like focal ischemia and neurodegenerative diseases. CO, produced by heme oxygenase, also functions as a neurotransmitter candidate. CO is involved in maintaining endogenous cGMP levels, mediating glutamate action at metabotropic receptors, and regulating chemosensory responses in the carotid body. Both NO and CO have expanded our understanding of synaptic transmission and the mechanisms underlying neuronal function.