CD137 (also called 4-1BB and TNFRSF9) has recently received attention as a therapeutic target for cancer and a variety of autoimmune and inflammatory diseases. Stimulating CD137 in vivo enhances CD8+ T cell-activity and results in strong immunosuppression in some contexts. This paradoxical phenomenon may be partially explained by the ability of CD137-stimulating reagents (usually agonistic monoclonal antibodies against) to over-activate T cells and other CD137-expressing cells. This overactivity is associated with deleting pathogenic T cells and B cells or generating a tolerogenic microenvironment. Recent studies, however, suggest that the biology of CD137 and its ligand (CD137L) are more complex, mainly due to bidirectional signaling bwtween CD137 and CD137L. Recent studies show that signaling through CD137L in non-hematopoietic cells such as epithelial cells and endothelial cells plays an essential role in sterile inflammation by regulating immune cell recruitment. One outstanding, and clinically important, issue is understanding how bidirectional signaling through CD137 and CD137L controls the vicious cycle of sterile inflammation (e.g., ischemia-reperfusion tissue injury and meta-inflammatory diseases).