Cell death is an essential process that shapes tissue development, enables the body to fight infection, and when perturbed, results in the onset of disease. Caspases are proteins that determine whether a cell will die. One such caspase, caspase-8, is a crucial regulator of cell death that is often perturbed in cancer, inflammatory bowel disease, and neurodegeneration. We have found that cells in the vicinity of inflammation inactivate caspases, to allow the cell to undergo a specific type of death called necroptosis. We are using recombinant protein and human cell-lines to determine the structural transition that occurs when caspases are oxidized by specific chemicals produced by immune cells. We have found that oxidation of caspase-8 and caspase-9 functional sites results in inactivation, amyloid fibril formation, and subsequent inflammatory cell death.1 This is the first known mechanism for activation of this type of cell death and one of the first examples of oxidation causing amyloid fibril formation. We have found that this oxidation crosslinks the active site cysteine, is highly specific and resistant to reduction, and shifts the oligomeric state during the formation of fibrils. We therefore suggest a functional role for caspase aggregation in allowing certain types of cell death to occur at sites of inflammation. Understanding the amyloid fibril formation of these cell death regulators is beginning to not only illuminate an important regulatory mechanism but also provide insight into inflammatory diseases.