The innate immune system is a highly sensitive organ of perception sensing any cell stress and tissue injury. Its major type of response to all potential inciting and dangerous challenges is inflammation and tissue repair and, if needed, induction of a supportive adaptive immune response, the aim always being to maintain homeostasis. However, although initially beneficial, innate immunity-mediated, protection-intended repair processes become pathogenic when they are exaggerated and uncontrolled, resulting in permanent fibrosis which replaces atrophic or dying tissue and may lead to organ dysfunction or even failure. In this sense, atherosclerosis and organ fibrosis reflect classical disorders caused by an overreacting innate immune system. Strikingly, these two pathologies dominate the development of chronic allograft dysfunction as the main clinical problem still left in transplantation medicine. Growing evidence suggests that acute and chronic allograft injuries, including alloimmune-, isoimmune-, nonimmune-, and infection-mediated insults, not only lead to cell death-associated graft atrophy but also activate the innate immune system which, over time, leads to uncontrolled intragraft fibrogenesis, thereby compromising allograft function. Acute and chronic allograft injuries lead to induction of damage-associated molecular patterns (DAMPs) which, after recognition by pattern recognition receptors, activate cells of the innate immune system such as donor-derived intragraft fibroblasts and vascular cells as well as recipient-derived graft-invading macrophages and leukocytes. It is mainly the orchestrated action and function of these cells that slowly but steadily metamorphose the originally life-saving allograft into a poorly functioning organ of marginal viability.