Although drug development has advanced for autoimmune diseases, many current therapies are hampered by adverse effects and the frequent destruction or inactivation of healthy cells in addition to pathological cells. Targeted autoimmune therapies capable of eradicating the rare autoreactive immune cells that are responsible for the attack on the body's own cells are yet to be identified. This Review presents a new emerging approach aimed at selectively destroying autoreactive immune cells by specific activation of tumour necrosis factor receptor 2 (TNFR2), which is found on autoreactive and normal T lymphocytes, with the potential of avoiding or reducing the toxicity observed with existing therapies.