The aim of this critical review is to address that the study of cognition and antipsychotics is not always driven by logic and that research into real pro-cognitive drug treatments must be guided by a better understanding of the biochemical mechanisms underlying cognitive processes and deficits. Many studies have established that typical neuroleptic drugs do not improve cognitive impairment. Atypical antipsychotics improve cognition, but the pattern of improvement differs from drug to drug. Diminished cholinergic activity has been associated with memory impairments. Why atypical drugs improve aspects of cognition might lie in their ability to increase dopamine and acetylcholine in the prefrontal cortex. An optimum amount of dopamine activity in the prefrontal cortex is critical for cognitive functioning. Another mechanism is related to procedural learning, and would explain the quality of the practice during repeated evaluations with atypical antipsychotics due to a more balanced blockage of D2 receptors. Laboratory studies have shown that clozapine, ziprasidone, olanzapine, and risperidone all selectively increase acetylcholine release in the prefrontal cortex, whereas this is not true for haloperidol and thioridazine. A few studies have suggested that cholinomimetics or AChE inhibitors can improve memory functions not only in Alzheimer's disease but also in other pathologies. Some studies support the role of decreased cholinergic activity in the cognitive deficits while others demonstrate that decreased choline acetyltransferase activity is related to deterioration in cognitive performance in schizophrenia. Overall, results suggest the hypothesis that the cholinergic system is involved in the cognitive dysfunctions observed in schizophrenia and that increased cholinergic activity may improve these impairments. Furthermore, a dysfunction of glutamatergic neurotransmission could play a key role in cognitive deficits associated with schizophrenia. Further meta-analysis of various clinical trials in this field is required to account for matters on the grounds of evidence-based medicine.