Neurocognitive research has focused on monoaminergic influences over broad behavior patterns. For example, dopamine (DA) generally facilitates informational transfer within limbic and cortical networks to promote reward-seeking behavior. Specifically, DA activity in prefrontal cortex modulates the ability for nonhuman primates and humans to perform spatial working memory tasks. Serotonin (5HT) constrains the activity of DA, resulting in an opposing relationship between DA and 5HT with respect to emotional and motor behaviors. A role for 5HT in constraining prefrontally guided spatial working memory (WM) processes in humans has not been empirically demonstrated but is a logical avenue for study if these principles of neurotransmitter activity hold within cortical networks. In this study, normal humans completed a visuospatial WM task under pharmacological challenge with (i) bromocriptine, a DA agonist and (ii) fenfluramine, a serotonin agonist, in a double-blind, repeated-measures, placebo-controlled design. Findings indicate that bromocriptine facilitated spatial delayed, but not immediate, memory performance. Fenfluramine resulted in impaired delayed spatial memory. These effects were not due to nonspecific arousal, attentional, sensorimotor or perceptual changes. These findings suggest that monoaminergic neurotransmitters (DA and 5HT) may interact within cortical networks to modulate the expression of specific cognitive behaviors, particularly effortful processes associated with goal-directed activity.