Receptor-interacting protein kinase-3 (RIPK3, or RIP3) is an essential protein in the "programmed" and "regulated" cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, and the findings of many reports have suggested that necroptosis is highly significant in health and human disease. This significance is largely because necroptosis is distinguished from other modes of cell death, especially apoptosis, in that it is highly proinflammatory given that cell membrane integrity is lost, triggering the activation of the immune system and inflammation. Here, we discuss the roles of RIPK3 in cell signaling, along with its role in necroptosis and various pathways that trigger RIPK3 activation and cell death. Lastly, we consider pathological situations in which RIPK3/necroptosis may play a role.