Z-DNA binding protein-1 (ZBP1) is a pathogen recognition receptor that recognises Z-form nucleic acids and drives cell death and inflammation. It is best known for its ability to detect Z-RNA released from viruses, including Influenza A Virus and Herpes simplex virus-1, and promote antiviral responses by triggering the apoptotic, necroptotic, and/or pyroptotic death of infected cells. Recent work has also shown that ZBP1 can be activated by host-dervied Z-RNA arising from endogenous retroviral elements. Recognition of these retroelements by ZBP1 may promote inflammation in inflammatory bowel disease (IBD) and other noncommunicable inflammatory diseases. Despite this growing interest in ZBP1, how it selectively promotes cell death induced by Z-nucleic acids while being superfluous to other closely related forms of cell death is unclear. To address this issue, we have characterised human cell culture models of apoptosis and necroptosis where the involvement of ZBP1 can be finely controlled. With these models, and by using immunoblotting, live/fixed cell imaging, and proteomic techniques, we are now defining the signalling complexes induced by ZBP1-dependent versus -independent death. We anticipate these approaches will uncover new and selective regulators of ZBP1-dependent cell death and signalling.