This chapter focuses on studies in which the interaction of sleep loss and caffeine on a variety of cognitive tests was examined. Caffeine effects on cognitive performance are dependent upon both the dose and the method used to deliver the caffeine. A variety of outcome measures have been used to assess the efficacy of caffeine during sleep loss. The commonly used measures are subjective and objective sleepiness. Short-term memory has been examined during sleep loss using several types of tasks including the Digit-Symbol Substitution Test (DSST), coding, short-term memory recall, and digit span. Numerous additional cognitive tests have been examined during sleep deprivation. The effects of caffeine during sleep loss have been examined over a large dose range. Administration of caffeine typically produces both physiological effects and mood changes. If caffeine use is terminated once tolerance develops, withdrawal (which includes symptoms such as headache, fatigue, and sleepiness) may occur.