Cell-based therapy has been viewed as a promising alternative to organ transplantation, but cell transplantation aimed at organ repair is not always possible. Here we show that the mouse lymph node can support the engraftment and growth of healthy cells from multiple tissues. Direct injection of hepatocytes into a single mouse lymph node generated enough ectopic liver mass to rescue the survival of mice with lethal metabolic disease. Furthermore, thymuses transplanted into single lymph nodes of athymic nude mice generated functional immune systems that were capable of rejecting allogeneic and xenogeneic grafts. Additionally, pancreatic islets injected into the lymph nodes of diabetic mice restored normal glucose control. Collectively, these results suggest the practical approach of targeting lymph nodes to restore, maintain or improve tissue and organ functions.