Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in adults and children. Predicting outcome after TBI is difficult, but it is important for acute management, counseling of family members, and provision of rehabilitation services. Serum biomarkers may be useful alone or in combination with clinical variables to predict outcome after TBI. This article reviews the potential uses of serum biomarkers for the clinician, current literature related to the use of serum biomarkers for outcome prediction after adult and pediatric TBI, limitations of the literature, and future direction for this field.