Given the difficulties of developing cognitive enhancers for schizophrenia and demonstrating their efficacy, we welcome a review of the measurement procedures and the clinical trial design recommendations developed through the collaboration of academics, industry, National Institute of Mental Health (NIMH), and U.S.A. Food and Drug Administration (FDA) representatives during the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) process. We provide a perspective from investigators who helped to lead the MATRICS initiative. We acknowledge some of the practical challenges in the use of the MATRICS Consensus Cognitive Battery (MCCB) while pointing out that others are overstated. We suggest that a brief MCCB might be used in phase III trials when phase II results had shown no negative impact on any MCCB cognitive domain. The complexities of requiring a functional co-primary measure are discussed. For clinical trial research design to evaluate monotherapies that might have both antipsychotic and cognition-enhancing properties, we agree that the original MATRICS design recommendations may need to be revised, as those recommendations focused on the evaluation of potential adjunctive cognitive enhancers. Horan et al provide a thoughtful summary of the current challenges in obtaining approval for a new drug designed to enhance cognition in schizophrenia.