The CD70/CD27 axis has gained increasing interest among the immunologists, because of its capacity to regulate immunity versus tolerance. Recent studies clearly show that expression of CD70 may prevent tolerance induced by antigen presentation in the steady-state, i.e., by nonactivated DCs. In addition, CD27 signaling appears critical for T cell expansion and survival and therefore, induction of long-term memory. It contributes to germinal center formation, B cell activation, and production of neutralizing antibodies but can also be subverted by viruses, in particular, during chronic infections. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, as in EAE, arthritis, and inflammatory bowel disease models, suggests that CD70 may be a target for immune intervention. Conversely, the potency of costimulation through CD27 suggests that the CD27/CD70 axis could be exploited for the design of anti-cancer vaccines.