This chapter examines the rationale for pharmacological cognitive enhancement, standard methods for trial design, candidate pharmacological mechanisms, compound selection strategies, and the results to date. Cognitive impairments arise from the central nervous system (CNS), with its complex array of neurotransmitters, cortical networks, and electrochemical activity. There are multiple neurotransmitters associated with cognitive performance in human and animal models. Transmitter manipulations can be beneficial or adverse and different receptor subtypes for the same transmitter can have opposite effects on the same cognitive processes. Drugs that reverse cognitive deficits caused by anticholinergic compounds such as scopolamine are often those seen to have potential for treatment of cognitive deficits in Alzheimer's dementia. The Food and Drug Administration (FDA) has imposed a six-month duration requirement for the active phase of acute treatment trials for cognitive enhancement in schizophrenia. Cognitive enhancement with serotonergic agonists and studies examined effects of active serotonergic agents.