Although chronic rejection is currently the main cause of long-term allograft failure, its pathogenesis remains elusive, hereby preventing the development of effective therapy. Recent advances in the comprehension of the pathophysiology of chronic inflammatory diseases could shed new light on the pathogenesis of chronic rejection. Lymphoid neogenesis is a mechanism responsible for the progressive organization of chronic inflammatory infiltrates into functional ectopic germinal centers, and has been evidenced recently in various pathological situations sharing a common feature: the failure of the immune response to eradicate the targeted antigen(s). Chronic rejection is such a situation as it results from a sustained alloimmune response against the donor's antigens that are constantly replenished by the grafted tissue. Accordingly, functional ectopic germinal centers develop within chronically rejected organs. This implies that, during chronic rejection, graft is at the same time the target and the site of elicitation of the alloimmune response.