The immune response evolved to destroy invading foreign microorganisms that pose a significant threat to life. Elimination of these foreign pathogens inevitably causes bystander damage to the host’s own tissues. As such, the immune system evolved the parallel function of promoting repair of tissues impacted by infection. The immune system’s support of tissue regeneration is now understood to span lifelong maintenance of tissue homeostasis in response to aseptic damage accumulated from wear and tear, through to promoting morphogenesis and limb regeneration in some species. Bone regeneration relies heavily on a coordinated interplay between the immune system and other cellular processes essential for tissue repair. The immune response plays a key role in coordinating the complex multistage process required for fracture healing with initial phases requiring proinflammatory immune cell actions with progressive transition to anti-inflammatory regenerative actions. Of relevance, understanding of the tissue regenerative opportunity of mesenchymal stem cells has transitioned from their engraftment within and integration into the repairing tissue, to their ability to modulate the inflammatory response. Evidence is accumulating that innate immune cells (specifically macrophages) and regulatory T cells are a promising means to promote bone regeneration with therapeutic opportunity spanning systemic bone loss, failed fracture repair and promoting biomaterial/orthopaedic implant integration. However, caution is needed, as the immune system is inherently dynamic and malleable. Its ability to promote regeneration is counterbalanced by the capacity of the same immune cells being able to mediate tissue destruction and/or program an inappropriate regenerative response, as demonstrated in heterotrophic ossification.