It has long been appreciated that the apoptotic activity of TNFα is context-dependent, and requires inhibition of NFκB signaling or de novo protein synthesis to be manifested in most normal cells in culture. Recent studies have uncovered an unexpected pro-apoptotic synergism between TNF cytokines and the CCN family of extracellular matrix proteins, which are dynamically expressed at sites of injury repair and inflammation. The presence of CCN1, CCN2, or CCN3 allows TNFα to induce apoptosis with high efficacy without perturbation of NFκB signaling or de novo protein synthesis, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. CCN proteins also enhance the cytotoxicity of other TNF family cytokines including LTα, FasL, and TRAIL. CCN proteins synergize with TNF cytokines through binding to integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation. Knockin mice that express a CCN1 mutant defective for binding α6β1-HSPG are severely blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. Thus, CCN proteins in the extracellular matrix microenvironment can provide the contextual cues for the cytotoxicity of TNFα and related cytokines, and profoundly influence their activity.