Hundreds of cerebroprotectants have failed in clinical trials despite promising results in pre-clinical model systems. The Stroke Preclinical Assessment Network (SPAN) sought to improve predictive success by implementing key elements of scientific rigor: blinding, randomization, adequate sample size, study in females and males, and use of animals with co-morbidities such as aging, hypertension, and diabetes. SPAN tested uric acid, tocilizumab, fingolimod, fasudil, veliparib, and remote ischemic conditioning in a multi-arm, multi-stage paradigm that included behavioral and imaging outcomes. Models included young, health mice, aging mice, spontaneously hypertensive rats, and mice with obesity-induced hyperglycemia. Final sample size will be over 3,000 subjects, making SPAN the largest pre-clinical assessment ever conducted in any disease area. Interventions were eliminated at each interim analysis for futility. SPAN invented and implemented procedures and protocols that will inform future pre-clinical assessment in a variety of diseases. At the time of ISC 2023, the final results of SPAN will be known, and SPAN 2.0 will have begun with up to 8 new interventions under study.