The progressive organization of cellular infiltrates into functional ectopic germinal centers (i.e. lymphoid neogenesis) has been recently evidenced in various chronic inflammatory diseases. Failure of the immune system to eradicate the targeted antigen(s) is a shared feature of all of the pathological situations associated with lymphoid neogenesis. Although necessary, inability of the immune system to eradicate the antigen(s) seems insufficient to trigger lymphoid neogenesis by itself. We propose that both defective lymphatic drainage of the inflamed tissue and enduring local antigenic stimulation are the crucial triggers of the cascade of events leading to lymphoid neogenesis. In turn, ectopic germinal centers prevent the restoration of lymph outflow by diverting inflammation-dependent lymphangiogenesis. Antigens and immune effectors are rerouted towards the neoformed ectopic lymphoid structures. A self-perpetuating feedback loop, which further sustains the development of the local immune response, is now imposed.