ZBP1 (also known as DAI) is a protein that activates RIPK3-dependent signalling via RIP homotypic interaction motif-dependent protein-protein interactions. ZBP1 also senses Z-form DNA and RNA via its two Za domains. ZBP1-RIPK3 mediated cell death plays an important role for anti-viral defence. We found that ZBP1 also contributes to inflammation by inducing RIPK3-dependent necroptosis and that RIPK1 acts via its RIP homotypic interaction motif (RHIM) to prevent ZBP1 activation in this context (Lin et al, Nature 2016). Our current work focuses on dissecting the mechanisms regulating the activation and function of ZBP1 in immunity and inflammation and its role in the pathogenesis of inflammatory diseases.