Caffeine is effective at restoring alertness and psychomotor vigilance during periods of sleepiness. Sleepiness can result from a number of causes, including normal fluctuations in alertness that occur throughout the day, more severe degradation of alertness that occurs during the overnight circadian trough, increased homeostatic sleep pressure that accumulates during periods of prolonged wakefulness, or some combination of these factors. This chapter explores the effectiveness of caffeine as a countermeasure to sleepiness in each of these situations. It explains the use of caffeine to overcome sleepiness and sustain alertness and performance during periods when sleep is not desired or must be avoided. When applied judiciously, caffeine appears to be a relatively safe, effective, and socially acceptable countermeasure to occasional unwanted sleepiness. However, like most drugs, optimal benefits from caffeine only emerge when it is used appropriately and with due consideration to both its positive and negative effects.