Worldwide, hard-to-heal lower limb wounds are estimated to affect 1.5–3% of the adult population with a treatment-related annual cost of $10 billion. Thus, chronic skin ulcers of the lower limb are a matter of economic and public concern. Over the years, multiple medical and surgical approaches have been proposed but they are still inadequate, and no effective therapy yet exists. Regenerative medicine and stem cell-based therapies hold great promise for wound healing. Recently, many plastic surgeons have studied the potential clinical application of adipose-derived stem cells (ASCs), which are a readily available adult stem cell population that can undergo multilineage differentiation and secrete growth factors that can enhance wound-healing processes by promoting angiogenesis, and hence increase local blood supply. ASCs have been widely studied in vitro and in vivo in animal models. However, there are few randomized clinical trials on humans, and these are still ongoing or recruiting patients. Moreover, there is no consensus on a common isolation protocol that is clinically feasible and which would ensure reproducible results. The authors aim to provide readers with an overview of the biological properties of ASCs as well as their clinical application, to help better understanding of present and future strategies for the treatment of hard-to-heal wounds by means of stem cell-based therapies.