This chapter focuses on the development of histamine receptor (H3R) antagonists and hypocretin agonists as emerging treatments of excessive daytime sleepiness (EDS). It also discusses the novel therapies in development for treatment of EDS including immunotherapy, thyrotrophin (TRH) analogues and promoters, and miscellaneous therapies. The long-term effects of H3R will determine if and how useful these drugs will be in the treatment of excessive daytime sleepiness in the setting of neurological disease, narcolepsy, idiopathic hypersomnia, or other chronic diseases. Histamine has long been known to have a key role in the regulation of sleep and wakefulness. One of the most important recent discoveries in narcolepsy research was the description of hypocretin deficiency to narcolepsy-cataplexy (NC). Systemic administration of hypocretin-1 in canines with narcolepsy produces increases in activity levels, wake times, reduces sleep fragmentation, and has a dose-dependent reduction in cataplexy.