•Innate immune signaling components (RIPK1, TAK1 and ZBP1) are critical regulators of inflammation and programmed cell death.•Innate signaling connected with pyroptosis, apoptosis, necroptosis, and PANoptosis promotes inflammatory diseases.•Understanding molecular mechanisms of programmed cell death provides new therapeutic targets to treat inflammatory diseases. The innate immune system, the first line of defense against pathogens and host tissue damage, initiates pro-inflammatory responses which, when dysregulated, promote inflammation to drive a broad range of autoimmune diseases. Immunomodulatory therapies have been developed to successfully treat several autoimmune diseases, but still many others lack effective treatments. Here, we explore recent advances in how the innate immune system contributes to autoinflammation, from the innate immune sensors that initiate immune responses to how this system regulates the activation of programmed cell death pathways including pyroptosis, apoptosis, necroptosis, and PANoptosis, which involves machinery from the pyroptotic, apoptotic, and necroptotic pathways. Recent advances in our understanding of innate immunity raise important considerations for developing new inflammatory disease treatments that target innate immune signaling and programmed cell death pathways.