Recent advances in medicine, intensive care and diagnostic imaging modalities have led to a pronounced reduction in deaths and disability resulting from traumatic brain injury. However, there are not sufficient findings to evaluate and quantify the severity of the initial and secondary processes destructive and therefore there are not effective therapeutic measures to effectively predict the outcome. For this reason, in recent decades, researchers and clinicians have focused on specific markers of cellular brain injury to improve the diagnosis and the evaluation of outcome. Many proteins synthesized in the astroglia cells or in the neurons, such as neuron-specific enolase, S100 calcium binding protein B, myelin basic protein, creatine kinase brain isoenzyme, glial fibrillary acidic protein, plasma desoxyribonucleic acid, brain-derived neurotrophic factor, and ubiquitin carboxy-terminal hydrolase-L1, have been proposed as potential markers for cell damage in central nervous system. Usually, the levels of these proteins increase following brain injury and are found in increasing concentrations in the cerebrospinal fluid depending on the injury magnitude, and can also be found in blood stream because of a compromised blood-brain barrier. In this review, we examine the various factors that must be taken into account in the search for a reliable non-invasive biomarkers in traumatic brain injury and their role in the diagnosis and outcome evaluation.