During the past several years, mesenchymal stem cells (MSCs) derived from adult tissue have rapidly moved from in vitro and animal studies into clinical trials as a therapeutic modality for a diverse group of clinical applications, including head and neck reconstruction. For many diseases, cell therapy could affect the underlying pathophysiologic processes through multiple pathways providing an advantage over current treatment modalities. There is an emerging body of evidence that MSCs have unique immunomodulatory properties in addition to the ability to differentiate into multiple tissue lineages which make them even more attractive for regenerative medicine. A variety of pre-clinical and clinical studies have shown that MSCs may have a useful role in tissue repair as well as engineering strategies in head and neck reconstructive surgery. Clinically, this has ranged from injection laryngoplasty to the implantation of a tracheal construct seeded with MSC-derived chondrocytes. Recent advances in stem cell immunobiology can offer insight in the multiple mechanisms through which MSCs could affect underlying pathophysiologic processes ranging from vocal fold scarring to composite tissue defects. Thorough evaluation of the current literature is necessary in understanding how MSCs could potentially revolutionize our approach to head and neck defects. The purpose of this review is to highlight the advances in MSC-based therapies in head and neck surgery, specifically laryngotracheal reconstruction. The clinical role of tissue-derived MSCs, though not well understood, holds promise for many therapeutic applications in regenerative medicine and reconstruction.