Receptor-interacting protein kinase-3 is essential for the cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, leading to significant consequences in inflammation and in diseases, particularly cancer. Necroptosis is highly proinflammatory compared with other modes of cell death because cell membrane integrity is lost, resulting in releases of cytokines and damage-associated molecular patterns that potentiate inflammation and activate the immune system. We discuss various ways that necroptosis is triggered along with its potential role in cancer and therapy.