Brain injury can exist in different forms; such conditions occur after mechanical trauma, such as traumatic brain injury (TBI) or after exposure to a number of recreational drugs such as MDMA, methamphetamine, or cocaine. Recent findings have provided some preliminary data showing that brain injury and drug abuse insults may share common pathway(s)leading to neuronal cell injury. Such pathways may be mediated by the activation of the protease families: the pronecrotic calpain and the proapoptotic caspase systems. These proteases can act on a number of substrates including the cytoskeletal proteins resulting in the breakdown products of such proteins can be used as biomarkers for brain injury insult (mechanical and chemical). The field of proteomics has been introduced as a new discipline for biomarker identification that allows for deciphering protein expression at very low concentrations. Having this in mind, neuroproteomics approach has been applied to identify the differential alterations of protein markers involved in two models of experimental traumatic brain injury as well as in drug abuse which showed high similarity in the underlying mechanisms leading to neuronal injury.