Heterotopic ossification (HO), including hereditary and acquired HO, is the formation of extraskeletal bone in skeletal muscle and surrounding soft tissues. Acquired HO is often caused by range of motion, explosion injury, nerve injury or burns. Severe HO can lead to pain and limited joint activity, affecting functional rehabilitation and quality of life. Increasing evidence shows that inflammatory processes and mesenchymal stem cells (MSCs) can drive HO. However, explicit knowledge about the specific mechanisms that result in HO and related cell precursors is still limited. Moreover, there are no effective methods to prevent or reduce HO formation. In this review, we provide an update of known risk factors and relevant cellular origins for HO. In particular, we focus on the underlying mechanisms of MSCs in acquired HO, which follow the osteogenic program. We also discuss the latest therapeutic value and implications for acquired HO. Our review highlights the current gaps in knowledge regarding the pathogenesis of acquired HO and identifies potential targets for the prevention and treatment of HO.