Cognitive deficits in schizophrenia are wide-ranging and associated with functional disability. Pharmacological treatment efforts specifically targeting cognition have been underway for over 20 years, with efforts shaped by the collaborative Measurement and Treatment Research to Improve Cognition in Schizophrenia effort. Despite considerable enthusiasm and dozens of attempts, there have only been two treatments that advanced to phase 3 approval studies. There are several possible reasons for these large numbers of failures and we will examine the importance of these efforts, the challenges associated with both schizophrenia itself and the recommended research strategies, and previous strategies that guided drug development. We will evaluate several “near misses” in terms of approval and the latest developments with new pharmacological mechanisms that may be promising for different reasons, when compared to previous drug development targets.