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Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint., Competing Interests: Author Disclosure Statement GLI has been reimbursed by the government, professional scientific bodies, and commercial organizations for discussing or presenting research relating to MTBI and sport-related concussion at meetings, scientific conferences, and symposiums. He has a clinical practice in forensic neuropsychology involving individuals who have sustained mild TBIs. He has received honorariums for serving on research panels that provide scientific peer review of programs. He is a co-investigator, collaborator, or consultant on grants relating to mild TBI funded by several organizations. He has received grant funding from pharmaceutical companies to do psychometric research using neuropsychological tests. He has received research support from neuropsychological test publishing companies in the past (not in the past 5 years). For the remaining authors, no competing financial interests exist. NDS receives salary support from a Vancouver Coastal Health Research Institute Clinician-Scientist Career Development Award. GLI acknowledges support from the INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD), Harvard Integrated Program to Protect and Improve the Health of NFLPA Members, and the Mooney-Reed Charitable Foundation. GTM acknowledges support from NIH U01 NS086090-01, DOD USAMRAA W81XWH-13-1-0441, DOD W81XWH-14-2-0176, and One Mind. This work is related to the TBI Endpoints Development Initiative and a grant entitled Development and Validation of a Cognition Endpoint for Traumatic Brain Injury Clinical Trials.