Wake-promoting agents (WPAs) are a class of drugs that primarily excite the cerebral cortex, with effects including promoting wakefulness, increasing alertness, enhancing attention, improving cognitive function, and reducing fatigue. The use of WPAs can be traced back hundreds of years, with traditional commonly used WPAs including caffeine and amphetamine stimulants. However, the contradictions between their efficacy and tolerability (such as drug dependence and cardiovascular side effects), as well as the clinical limitations of insufficient efficacy for excessive daytime sleepiness (EDS) in specific etiologies (such as narcolepsy), have driven the development of novel WPAs. Compared to traditional drugs, novel WPAs such as modafinil, solriamfetol, and pitolisant have become important breakthroughs in this field due to their safety advantages. The discovery of orexin receptor agonists has also opened new directions for WPA development. This article reviews the past, present, and future of WPA development, aiming to provide a reference basis for formulating individualized treatment plans in clinical practice.