Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT(1A) receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.