Mild traumatic brain injury (mTBI) results from a transfer of mechanical energy into the brain from traumatic events such as rapid acceleration/deceleration, a direct impact to the head, or an explosive blast. Transfer of energy into the brain can cause structural, physiological, and/or functional changes in the brain that may yield neurological, cognitive, and behavioral symptoms that can be long-lasting. Because mTBI can cause these symptoms in the absence of positive neuroimaging findings, its diagnosis can be subjective and often is based on self-reported neurological symptoms. Further, proper diagnosis can be influenced by the motivation to conceal or embellish signs and/or an inability of the patient to notice subtle dysfunctions or alterations of consciousness. Therefore, appropriate diagnosis of mTBI would benefit from objective indicators of injury. Concussion and mTBI are often used interchangeably, with concussion being primarily used in sport medicine, whereas mTBI is used in reference to traumatic injury. This review provides a critical assessment of the status of current biomarkers for the diagnosis of human mTBI. We review the status of biomarkers that have been tested in TBI patients with injuries classified as mild, and introduce a new concept for the discovery of biomarkers (termed symptophenotypes) to predict common and unique symptoms of concussion. Finally, we discuss the need for biomarker/biomarker signatures that can detect mTBI in the context of polytrauma, and to assess the consequences of repeated injury on the development of secondary injury syndrome, prolongation of post-concussion symptoms, and chronic traumatic encephalopathy.