As a result of reading this article, physicians should be able to:

• 1.
  Update the current knowledge about candidate cell populations as heterotopic ossification (HO) contributors.
• 2.
  Understand the potential limitations of the experimental designs and techniques underlying the identification of putative HO contributors.
• 3.
  Clarify the confusion about the phenotypes of candidate populations in the literature.
• 4.
  Contrast the fundamental cellular differences between HO and normal skeletogenesis to identify potential disease-specific targets.

Heterotopic ossification (HO), acquired or hereditary, is featured by the formation of bone outside of the normal skeleton. Typical acquired HO is a common, debilitating condition associated with traumatic events. Cardiovascular calcification, an atypical form of acquired HO, is prevalent and associated with high rates of cardiovascular mortality. Hereditary HO syndromes, such as fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, are rare, progressive, life-threatening disorders. The cellular origins of HO remain elusive. Some bona fide contributing cell populations have been found through genetic lineage tracing and other experiments in vivo, and various other candidate populations have been proposed. Nevertheless, because of the difficulties in establishing cellular phenotypes in vivo and other confounding factors, the true identities of these populations are still uncertain. This review critically evaluates the accumulating data in the field. The major focus is on the candidate populations that may give rise to osteochondrogenic lineage cells directly, not the populations that may contribute to HO indirectly. This issue is important not solely because of the clinical implications, but also because it highlights the basic biological processes that govern bone formation. [Orthopedics. 2014; 37(5):329–340.]