Mild traumatic brain injury (TBI), which is defined as a head trauma resulting in a brief loss of consciousness and/or alteration of mental state, is usually benign, but occasionally causes persistent and sometimes progressive symptoms. Whether a threshold for the amount of brain injury and/or individual vulnerability might contribute to the development of these long-term consequences is unknown. Furthermore, reliable diagnostic methods that can establish whether a blow to the head has affected the brain (and in what way) are lacking. In this Review, we discuss potential biomarkers of injury to different structures and cell types in the CNS that can be detected in body fluids. We present arguments in support of the need for further development and validation of such biomarkers, and for their use in assessing patients with head trauma in whom the brain might have been affected. Specifically, we focus on the need for such biomarkers in the management of sports-related concussion, the most common cause of mild TBI in young individuals, to prevent long-term neurological sequelae due to concussive or subconcussive blows to the head.