Lower limb exoskeletons (EXOs) may be devised as an ambulation device, as a rehabilitation tool or may be aimed at allowing both objectives. 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, in this area the old wheelchair is still largely winning the challenge. 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. 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. These challenges will be presented from a clinical rehabilitation perspective and expectations and critics discussed.