Macacine herpesvirus 1 or “Herpes B virus” (BV) naturally infects macaques, and Papiine herpesvirus 2 (HVP2) infects baboons. BV and HVP2 are closely related to Herpes simplex virus (HSV)-1 and -2 and all four viruses cause a similar self-limiting infection in their natural, immunocompetent hosts. However, these viruses are often associated with extreme neurovirulence following cross-species transmission, for example BV can cause encephalitis in humans with a mortality rate of ~80%. The HSV encephalitis in humans has been associated with genetic defects in innate immune signalling molecules that contain RIP homotypic interaction motifs (RHIMs). RHIM-containing proteins play key roles in cell death and proinflammatory pathways and HSV-1 and -2 encode viral decoy RHIMs in the UL39 gene that can modulate these signalling pathways in a species-dependent manner. The neurovirulence of HVP2 in mice has been mapped to the UL39 gene and RHIM sequences have been identified in the UL39 genes of BV and HVP2, however their function/s have not yet been characterised. Our recent focus has been on determining if the UL39 genes of BV and HVP2 encode functional viral RHIMs capable of modulating host RHIM signalling pathways. We have shown that the UL39 genes of both BV and HPV2 can significantly impair NF-kB pathway activation in a RHIM-dependent fashion. We are now exploring the ability of these viral RHIM-containing proteins to modulate RHIM-mediated cell death in human and murine cells. This work expands our knowledge of viral RHIMs capable of interfering with human RHIM signalling and may help us better understand the inter-species neurovirulence of herpesviruses.