Behavioral states alternate between wakefulness and sleep, which is further subdivided into rapid‐eye‐movement sleep and non‐rapid‐eye‐movement sleep. Waking and sleep states are highly complex processes that are elegantly orchestrated by fine‐tuned neurochemical changes, including the neurotransmitters and neuromodulators glutamate, acetylcholine, γ‐amino‐butyric acid, norepinephrine, dopamine, serotonin, histamine, hypocretin, melanin concentrating hormone, adenosine, and melatonin. However, as highlighted in this brief overview, no single neurotransmitter or neuromodulator, but rather their complex interactions within organized neuronal ensembles, regulate waking and sleep states and drive their transitions. Dysregulation of and medications interfering with these neurochemical systems lead to sleep‐wake disorders and functional changes of wakefulness and sleep. The neurochemical pathways presented here, thus, are aimed to provide a conceptual framework for the understanding of the effects of currently used medications on wakefulness and sleep.