Many components of the vertebrate immune system have evolved with dual, interrelated functions of both protecting injured tissues from infection and providing for tissue maintenance and repair of injuries. The capacity for organ regeneration, prominent among invertebrates and certain phylogenically primitive vertebrates, is poorly developed in mammals. We have proposed that evolution of the mammalian immune system has produced inflammatory cellular interactions at sites of injury which have optimized tissue defense and facilitated tissue repair, but that these improvements included concomitant loss of regenerative capacity. This chapter briefly reviews work in two regenerating systems: scar-free repair of fetal mammalian skin and regeneration of amputated limbs in larval frogs. In both organs the potential to regenerate anatomically and functionally complete new structures is lost gradually during ontogeny and this loss coincides with development of an immune system producing an inflammatory response in injured tissues. Failure of organ regeneration has long been associated with scarring or fibrosis and this phenomenon is a direct result of inflammatory interactions of immune cells and fibroblasts at sites of injury. Several aspects of immunity related to repair are reviewed, including the importance of antigen-presenting cells and lymphocytes, relevant cytokines and growth factors released by these and other cells, immune functions of extracellular matrix components, and immunological functions of fibroblasts. Skin repair in various transgenic mouse models has been especially informative. Further study of immune mechanisms associated with the loss of regenerative capacity in the skin and amphibian limb will be useful for efforts to promote mammalian organ regeneration.