There has been remarkable progress in the last 20 years in understanding mechanisms that underlie the success of axonal regeneration in the peripheral nervous system, and the failure of axonal regeneration in the central nervous system. Following the identification of these underlying mechanisms, several distinct therapeutic approaches have been tested in in vivo models of spinal cord injury (SCI) to enhance central axonal structural plasticity, including the therapeutic administration of neurotrophic factors. While several tested mechanisms apparently enhance axonal growth, more recent, properly controlled studies indicate that experimental approaches to combine therapies that target distinct neural mechanisms achieve greater axonal growth than therapies applied in isolation. The search for combination therapies that optimize axonal growth after SCI continues.