A failure to adapt to novel or changing environmental demands is a core feature of a wide variety of neuropsychiatric disorders as well as the normal states of stress and fatigue. We review the neurochemistry of cognitive control, which has been associated primarily with the prefrontal cortex. Many drugs affect the functioning of the prefrontal cortex, but the direction and extent of drug effects vary across individuals and tasks. Apparently paradoxical effects are often observed, where the same medication causes both cognitive enhancement as well as cognitive side effects. We review neurobiological research that is beginning to elucidate the nature of these contrasting effects and the factors underlying the large variability across individuals and behaviours. The work has considerable implications for the understanding of and treatment development for abnormalities such as Parkinson's disease, attention deficit hyperactivity disorder and drug addiction.