A diversity of immune tolerance mechanisms have evolved to protect normal tissues from immune damage. Immune regulatory cells are critical contributors to peripheral tolerance. These regulatory cells, exemplified by the CD4(+)Foxp3(+) regulatory T (Treg) cells and a recently identified population named myeloid-derived suppressor cells (MDSCs), regulate immune responses and limiting immune-mediated pathology. In a chronic inflammatory setting, such as allograft-directed immunity, there may be a dynamic "cross-talk" between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage. CTLA4-B7-based interaction between the two branches may function as a molecular "bridge" to facilitate such "cross-talk." Understanding the interplays among Treg cells, innate suppressors, and pathogenic effector T (Teff) cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immunosuppressive elements in the innate and adaptive immune system. Successful development of localized strategies of regulatory cell therapies could circumvent the requirement for very high number of cells and decrease the risks associated with systemic immunosuppression. To realize the potential of innate and adaptive immune regulators for the still elusive goal of immune tolerance induction, adoptive cell therapies may also need to be coupled with agents enhancing endogenous tolerance mechanisms.