This review examines the modulatory effects of catecholamine neurotransmitters (norepinephrine and dopamine) on prefrontal cortical (PFC) function, particularly in relation to executive functions such as working memory, attentional set formation, reversal learning, and response inhibition. The authors discuss the dissociable effects of pharmacological manipulations of these systems on various cognitive tasks in rodents, nonhuman primates, and humans, using techniques ranging from microiontophoresis to functional magnetic resonance imaging (fMRI). They highlight the state-dependent nature of these effects, suggesting new ways to conceptualize fronto-executive functions and implications for understanding mental illness and its treatment. The review also explores the role of monoamines in cognitive flexibility, inhibitory control, and the genetic basis of mental illness, emphasizing the potential of monoamine-based treatments for conditions like ADHD, bipolar disorder, and schizophrenia.This review examines the modulatory effects of catecholamine neurotransmitters (norepinephrine and dopamine) on prefrontal cortical (PFC) function, particularly in relation to executive functions such as working memory, attentional set formation, reversal learning, and response inhibition. The authors discuss the dissociable effects of pharmacological manipulations of these systems on various cognitive tasks in rodents, nonhuman primates, and humans, using techniques ranging from microiontophoresis to functional magnetic resonance imaging (fMRI). They highlight the state-dependent nature of these effects, suggesting new ways to conceptualize fronto-executive functions and implications for understanding mental illness and its treatment. The review also explores the role of monoamines in cognitive flexibility, inhibitory control, and the genetic basis of mental illness, emphasizing the potential of monoamine-based treatments for conditions like ADHD, bipolar disorder, and schizophrenia.