Purinoceptor signaling, as a crucial mode of cellular signal transduction, has garnered significant attention for its roles in various pathophysiological conditions. Numerous ligands that regulate purinoceptor function have been extensively used in fundamental research and have shown immense therapeutic potential in treating various cardiovascular diseases, neurodegenerative diseases, pain, cancer, diabetes, depression, and autism. A limited number of studies have found that nicotinamide adenine dinucleotide phosphate (NADPH) can regulate certain purinoceptor subtypes and further influence downstream signal transduction. This chapter focuses on elucidating how NADPH regulates purinoceptor signaling and its potential role as a novel neurotransmitter.