Few specific therapeutic targets exist to manage brain injury, despite the prevalence of stroke or traumatic brain injury. With traumatic brain injury, characteristic neuronal changes include axonal swelling and degeneration, and the loss of synapses, the sites of communication between neurons. This is followed by axonal sprouting and alterations in synaptic markers in recovery. The resulting changes in neuronal connectivity are likely to contribute to the effects of traumatic brain injury on cognitive functions and the underlying mechanisms may represent points of therapeutic intervention. In agreement, animal studies implicate adhesion and signaling molecules that organize synapses as molecular players in neuronal recovery. In this article, the authors focus on the role of cell surface interactions in the recovery after brain injury in humans and animals. The authors review cellular and synaptic alterations that occur with injury and how changes in cell adhesion, protein expression and modification may be involved in recovery. The changes in neuronal surface interactions as potential targets and their possible value for the development of therapeutics are also discussed.