Heterotopic ossification (HO), or the abnormal development of bone tissue in soft-tissue locations, can be physically debilitating and clinically devastating. For unclear reasons, HO is highly associated with burn injury. The objective of this review is to summarize 1) cells that are responsible for HO, 2) in vitro and in vivo models of HO and how they have contributed to our current knowledge of the disease process, 3) the effects of the adipose compartment on HO, 4) the effects of inflammation on HO, and 5) the effects of mesenchymal stem cells (MSCs) on HO. Preclinical models of HO suggest several possible mechanisms for the development of this pathologic process, including progenitor cell differentiation and paracrine modulation of local inflammatory responses. Further studies are needed to elucidate the molecular mechanisms driving HO so that targeted therapies can be developed. Current literature supports a role for MSCs in modulating heterotopic bone formation, and direct manipulation of MSCs might one day be used to prevent and treat HO. (J Burn Care Res 2012;33:463-470).