TNFalpha plays key roles in the regulation of inflammation, cell death, and proliferation and its signaling cascade cross-talks with the insulin signaling cascade. PKCdelta, a novel PKC isoform, is known to participate in proximal TNFalpha signaling events. However, it has remained unclear whether PKCdelta plays a role in distal TNFalpha signaling events. Here we demonstrate that PKCdelta is activated by TNFalpha in a delayed fashion that is temporally associated with JNK activation. To investigate the signaling pathways activating PKCdelta and JNK, we used pharmacological and genetic inhibitors of NFkappaB. We found that inhibition of NFkappaB attenuated PKCdelta and JNK activations. Further analysis revealed that ER stress contributes to TNFalpha-stimulated PKCdelta and JNK activations. To investigate the role of PKCdelta in TNFalpha action, we used 29-mer shRNAs to silence PKCdelta expression. A reduction of ~90% in PKCdelta protein levels reduced TNFalpha-stimulated stress kinase activation, including JNK. Further, PKCdelta was necessary for thapsigargin-stimulated JNK activation. Because thapsigargin is a potent inducer of ER stress, we determined whether PKCdelta was necessary for induction of the UPR. Indeed, a reduction in PKCdelta protein levels reduced thapsigargin-stimulated CHOP induction, a hallmark of the UPR, but not BiP/GRP78 induction, suggesting that PKCdelta does not globally regulate the UPR. Next, the role of PKCdelta in TNFalpha mediated cross-talk with the insulin signaling pathway was investigated in cells expressing human IRS-1 and a 29-mer shRNA to silence PKCdelta expression. We found that a reduction in PKCdelta protein levels reversed the TNFalpha-mediated reduction in insulin-stimulated IRS-1 Tyr phosphorylation, Akt activation, and glycogen synthesis. In addition, TNFalpha-stimulated IRS protein Ser/Thr phosphorylation and degradation were blocked. Our results indicate that: 1) NFkappaB and ER stress contribute in part to PKCdelta activation; 2) PKCdelta plays a key role in the propagation of the TNFalpha signal; and 3) PKCdelta contributes to TNFalpha-induced inhibition of insulin signaling events.