Advances in medical and rehabilitative care now allow the 10–12,000 individuals who suffer spinal cord injuries each year in the United States to lead productive lives of nearly normal life expectancy, so that the numbers of those with chronic injuries will approximate 300,000 at the end of the next decade. This signals an urgent need for new treatments that will improve repair and recovery after longstanding injuries. In the present report we consider the characteristics of the chronically injured spinal cord that make it an even more challenging setting in which to elicit regeneration than the acutely injured spinal cord and review the treatments that have been designed to enhance axon growth. When applied in the first 2 weeks after experimental spinal cord injury, transplants, usually in combination with supplementary neurotrophic factors, and possibly modifications of the inhibitory central nervous system environment, have produced limited long-distance axon regeneration and behavioral recovery. When applied to injuries older than 4 weeks, the same treatments have almost invariably failed to overcome the obstacles posed by the neurons’ diminished capacity for regeneration and by the increasing hostility to growth of the terrain at and beyond the injury site. Novel treatments that have stimulated regeneration after acute injuries have not yet been applied to chronic injuries. A therapeutic strategy that combines rehabilitation training and pharmacological modulation of neurotransmitters appears to be a particularly promising approach to increasing recovery after longstanding injury. Identifying patients with no hope of useful recovery in the early days after injury will allow these treatments to be administered as early as possible.