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Patients with severe peripheral artery disease (PAD) who are not candidates for revascularization have poor prognosis. Cell therapy using peripheral blood-derived or bone marrow-derived mononuclear cells, mesenchymal stem cells, or marker-specific subsets of bone marrow cells with angiogenic properties may hold promise for no-option PAD patients. Injected cells may exert beneficial actions by enhancing local angiogenesis (either through maturation of endothelial progenitors, or through secretion of angiogenic mediators), or by transducing cytoprotective signals that preserve tissue structure. Despite extensive research, robust clinical evidence supporting the use of cell therapy in patients with critical limb ischemia is lacking. Larger, well-designed placebo-controlled clinical trials did not support the positive results of smaller less rigorous studies. There is a need for high-quality clinical studies to test the effectiveness of cell therapy in PAD patients. Moreover, fundamental cell biological studies are needed to identify the optimal cell types, and to develop strategies that may enhance homing, survival and effectiveness of the injected cells.