Clinical trials for traumatic brain injury (TBI) have not successfully produced a new therapeutic for neuroprotection or neurorestoration, despite multiple attempts. Stem cell–based therapies and/or cellular therapies have been developed over the past 20 years such that clinical trials are now in Phase II and III stages for neurologic diseases such as TBI and stroke. Many of the vexing issues from past clinical failures still exist today, namely, preclinical data that may not translate to clinical trial because of design and injury heterogeneity that poorly stratifies enrolled patients. Recognition of these problems has led us to advocate for outcome measures that are clinically meaningful, but do not represent a global functional “score.” Specifically, we seek to measure those early physiologically relevant outcomes (intracranial pressure, edema, and therapeutic intensity) and later structural outcomes in regions of interest that are linked to putative mechanisms of action of cell based therapies. Early approval of therapeutics that are successful by these metrics would then allow further access to treatments that could be further tested via patient registries and other surveillance for ultimate adoption. Continuing to do the same thing with each iterative trial will assure the same results.