Programmed cell death is a basic cellular process that is critical to maintaining tissue homeostasis. In contrastto apoptosis, necrosis was previously regarded as an unregulated and uncontrollable process. However, as researchhas progressed, necrosis, also known as necroptosis or programmed necrosis, is drawing increasing attention,not least becasu of its possible impications for cancer research. Necroptosis exhibits a unique signaling pathwaythat requires the involvement of receptor interaction protein kinases 1 and 3 (RIP1 and RIP3), mixed lineagekinase domain-like (MLKL), and phosphoglycerate mutase 5 (PGAM5) and can be specifically inhibited bynecrostatins. Not only does necroptosis serve as a backup cell death program when apoptosis is inhibited, but itis now recognized to play a pivotal role in regulating various physiological processes and the pathogenesis of avariety of human diseases such as ischemic brain injury, immune system disorders and cancer. The control ofnecroptosis by various defined trigger factors and signaling pathways now offers the opportunity to target thiscellular process for therapeutic purposes. The purpose of this paper is to review current findings concerning theconnections between various trigger factors and the RIP1/RIP3 signaling pathway as it relates to necroptosis.