When three independent groups reported in 2009 that RIPK3 is the critical mediator of necroptosis [39-41], several preclinical in vivo models were used to investigate RIPK3-deficient mice that had been reported in 2004 to have no overt spontaneous phenotype . The group of Francis Chan has demonstrated that RIPK3-ko mice are susceptible to vaccinia-virus infections . Whereas wild-type mice regularly survive a viral load, RIPK3-ko mice died within the first 2 weeks of exposure. Importantly, vaccinia virus expresses an inhibitor of caspase-8. While loss of functional caspase-8 triggered the necroptotic signal in the wild-type mice, the genetic absence of RIPK3 in susceptible mice prevented the necroptotic signal that would have otherwise cleared infected cells. Consistent with this, viral titers increased to extraordinarily high levels in RIPK3-ko mice whereas wild-type mice were able to suppress titers to moderate levels . Interestingly murine cytomegalovirus appears to have adapted to this second-line host defense. Like vaccinia virus, it expresses an inhibitor of caspase-8, but also the viral protein M45, which contains a RHIM-domain that interferes with the RIPK1–RIPK3 interaction and the formation of Complex IIb [43, 44]. As striking as these results were, they prompted an eminent next question: Can this pathogen defense mechanism, when activated by a nonphysiological stimulus, also trigger unintended, potentially harmful consequences? RIPK3-deficient mice were demonstrated to be protected from a cerulein-induced pancreatitis [39, 40], a preclinical model of necrotic pancreatitis and a relatively common and devastating clinical problem in critically ill patients. Currently, there are no effective or specific therapeutic approaches for treatment. Unfortunately, while interference with necroptosis remains as potential therapy, clinical studies testing the RIPK1-inhibitor Nec-1 have been disappointing , suggesting that inhibition of RIPK1's kinase activity is not sufficient to block the damage in patients or that necrostatin does not inhibit RIPK1's kinase activity to the extent that is required in patients to reach clinical benefit. High hopes have therefore emerged for compounds that directly target RIPK3. Comparable to the results found in the model of necrotizing pancreatitis, inflammatory bowel disease generally remains undefined as to etiology but injury is promoted by robust interactions of various immune cells with intestinal epithelia. Two reports have investigated the role of necroptosis in this setting. The first report conditionally deleted FADD (FADD-deficient mice die in utero) from intestinal epithelial cells (IECs) . This was shown to be due to spontaneous necroptotic cell death because concomitant genetic absence of RIPK3 completely prevented the inflammation in these mice. Conditional depletion of caspase-8 in IECs similarly activated the necroptotic pathway, resulting in bowel inflammation with features of Crohn's disease . In line with the results obtained with mice deficient for FADD in IECs, injury following in mice deficient for caspase-8 in IECs was also completely prevented in mice in which RIPK3 was not present . In atherosclerotic prone, LDL receptor-deficient mice, macrophages cause severe necrotic damage after mice are fed a high fat “western” diet for 16 weeks . However, on a RIPK3-deficient background, this phenotype was markedly reduced. A similar protective effect has been observed in mice that are deficient in apolipoprotein E (ApoE-ko) that were crossed to a RIPK3-deficient background given a high-fat diet. Importantly, inhibition of caspase-8 and application of oxidized LDL strongly promoted invading macrophages, capacity for RIPK3-dependent necroptosis. Therefore, necrotic lesions in atherosclerosis appear to be at least partly caused by RIPK3-dependent necroptosis , a phenotype that was also described for ethanol-induced necrosis in hepatocytes. A recent report has confirmed a necroptotic component in this setting by utilizing RIPK3-deficient mice . Not only RIPK3-ko mice were protected from hepatocyte injury and steatosis, but also expression of proinflammatory cytokines was reduced, supporting a role of necroptosis released CDAMPs in promoting immune responses (see below). Comparable to conditional depletion of caspase-8 in IECs, which resulted in a Crohn's disease-like phenotype, liver-specific knockout of caspase-8 resulted in severe nonapoptotic liver injury . In addition to the above-mentioned diseases, necrotic cell death is a hallmark of retinal detachment. It has been demonstrated that in this specialized compartment, both apoptosis and necroptosis are triggered simultaneously (one cell dies by apoptosis, the next one dies by necroptosis) . The same group has now confirmed that cones, but not rods, undergo necroptosis in their model of retinitis pigmentosa . These data support the concept that PCD and RN are not mutually exclusive programs and they may occur in the same organ, following the same stimulus. This is similarly observed in kidneys after IRI (see below), but mechanistic explanations in kidney injury remain unclear. The complexity of multiple necrotic cell death pathways is highlighted in the complex pathophysiology of sepsis, a leading cause of mortality in intensive care patients. Endotoxin triggers massive release of TNF-α and other pro-inflammatory cytokines, which leads to nitric oxide generation and unsupportable low blood pressure. RIPK3-deficient mice are protected from lethal TNF-α-mediated shock [45, 53]. This model attracted considerable attention when it was demonstrated by Cauwels et al  in that the pan-caspase inhibitor zVAD, which may have been expected to provide a benefit by blocking TNF-α effect, accelerated rather than prevented death. When RIPK3 was later identified as the mediator of necroptosis and activated by caspase-8 inhibition, these results could of course be reconciled. However, conflicting results remain in the literature about the clinical utility of Nec-1 in this sepsis model .