Immune and tissue homeostasis is achieved through balancing signals that regulate cell survival, proliferation, and cell death. Recent studies indicate that certain cell death programs can stimulate inflammation and are often referred as 'immunogenic cell death' (ICD). ICD is a double-edged sword that can confer protection against pathogen infection but also cause tissue damage. Necroptosis is a key ICD module that has been shown to participate in host defense against pathogen infection, tissue homeostasis, and cancer response to immunotherapy. Here, we will review recent findings on the regulation of necroptosis signaling and its role in pathogen infection, tissue homeostasis, and cancer.