This chapter provides a brief overview of some of the experimental challenges to obtain reliable pharmacological magnetic resonance imaging (phMRI) data, and summarizes the published literature. The chapter offers some plausible mechanistic insights into biological processes that mediate the effects of alerting medications, generically termed stimulants. The effect of sleep deprivation on functional connectivity within the default mode network and on brain regions typically activated during cognitive tasks was studied in 26 healthy participants. Nicotine or nicotinic stimulation decreases the activity in the default mode network. The alerting effects of cholinergic stimulation are well recognized, but clinical use in conditions of excessive daytime sleepiness has not been readily possible or even well studied. Repetitive consecutive testing using functional MRI (fMRI) has shown a progressive loss of functional activation, predominantly in the prefrontal cortex using a working memory 2-back task, which is prevented by modafinil and amphetamine treatment.