Spinal cord injury (SCI) is a traumatic event with a global incidence of 23 cases per million, representing 180,000 cases per annum worldwide. Recovery of locomotion is a main priority for spinal cord-injured patients. In addition to overcoming the obvious mobility and social issues related to the inability to stand or walk, regular ambulation may profoundly combat secondary medical problems associated with lack of weight-bearing activity in SCI patients. Lower limb exoskeletons (EXOs) may be devised as an ambulation device, as a rehabilitation tool or may be aimed at allowing both objectives living. Regarding rehabilitation, it is worth noticing that EXOs also provide a perfect environment for precise assessing of rehabilitation protocols and effects. Different is the case of EXO for mobility, where the old wheelchair is still largely winning the challenge: existing exoskeletons have limitations with respect to affordability, size, weight, speed, and efficiency, which may reduce their functional application. In all functional areas (velocity, safety, portability, acceptance as well as autonomy in the ADL) none of today EXOs can compete with the performances of an average wheelchair. However, EXO usage requires learning, and brain changes associated with tool usage introduce the human in the loop concept, a key aspect of clinical relevance for EXO usage. At present, interesting data on the biological mechanisms and rehabilitation relevance of embodiment are providing hints for guiding rehabilitation. In this chapter, these challenges will be presented from a clinical rehabilitation perspective and expectations and critics discussed.