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Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades, yet the current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients, and have significant overlap with unrelated disease states. A careful review of current treatment guidelines for TBI further highlights the potential utility of a blood-based TBI biomarker panel in augmenting clinical decision making. Numerous expert reviews on blood-based TBI biomarkers have been published but a close look at the methods used and the astonishing paucity of validation and quality control data has not been undertaken from the vantage point of the clinical laboratory. Further, the field of blood-based TBI biomarker research has failed to adequately examine sex and gender differences between men and women with respect to the clinical care settings, as well as differences in physiological outcomes of TBI biomarker studies. Discussions of triedand-true laboratory techniques in addition to a few new ones already operating in the clinical laboratory are summarized with a consideration of their utility in TBI biomarker assessment. In the context of TBI biomarkers, the central concerns discussed in this review are the readiness of the clinical laboratory, the willingness of the research environment and the inherent ability of each to radically affect patient outcomes in TBI.