Background: Bioengineered and allograft-derived skin substitutes are increasingly available and marketed for use in the healing of chronic wounds. Plastic surgeons should have evidence-based information available to guide their use of these products. The authors systematically reviewed the literature to determine the published outcomes and effectiveness of different skin substitutes for healing chronic foot ulcers. Methods: A broad literature search of the MEDLINE, EBSCO, EMBASE, and the Cochrane Central Register of Controlled Trials databases was undertaken. Relevant studies were selected by three independent reviewers to include randomized controlled trials or systematic reviews examining the use of skin substitutes on foot ulcers. Results were narrowed further by the application of predetermined inclusion and exclusion criteria. Studies were assessed for quality and data were extracted regarding study characteristics and objective outcomes. Results: Of an initial 271 search results, 15 randomized controlled trials, one prospective comparative study, and five systematic reviews were included in the systematic review. Most of the included clinical studies were of moderate to low quality by objective standards, and reported results using cell-based skin substitutes. The primary outcome examined, success rate of complete healing, was equivalent to or better than that of standard therapy for all skin substitutes examined. Conslustions: A convincing body of evidence supports the effectiveness of living cell-based skin substitutes as an adjunctive therapy for increasing the rate of complete healing in chronic foot ulcers when basic tenets of wound care are also being implemented. Acellular skin substitutes also show some promise for treatment of foot wounds but require further study.