Abstract: NETosis is a form of programmed cell death in which neutrophils de-condense and release their chromatin in complex with cytotoxic granule proteins to form Neutrophil Extracellular Traps (NETs). NETs ensnare and kill pathogens, but they also damage adjacent tissue and activate adaptive immune responses to NET proteins. We have observed a pro-NETosis gene signature in multiple patient data sets and have measured NETs in patient biopsies from several inflammatory diseases. While NETosis is likely to be dependent on many factors, peptidyl arginine deiminase 4 (PAD4) has emerged as a key regulator in this process. Our results suggest current PAD4 inhibitors are insufficient to serve as tool compounds, let alone drugs that may lead to autoimmune disease resolution. Our current efforts focus on building high content imaging methods to measure NETosis and identity novel PAD4 inhibitors.