In vitro work has defined the TNF receptor family member CD27 as a T and B cell co-stimulatory molecule. Its activity is governed by the transient availability of its TNF-like ligand CD70 on lymphocytes and dendritic cells. Recent studies, enforcing or abrogating CD27 function by genetic or protein intervention in mouse models have revealed key contributions of the CD27–CD70 system to effector and memory T cell formation, which is probably based on improved cell survival. The stimulatory effects of CD27 on B cell function appear to oppose those of CD70, which also has a signaling role. Targeting CD27–CD70 for therapy is attractive but should take into account the fact that constitutive CD27 stimulation culminates in lethal immunodeficiency.