Rabbit Haemorrhagic Disease Virus (RHDV) is of worldwide significance for both, domestic and wild rabbits (Oryctolagus cuniculus). While the loss of natural populations of wild rabbits in south-western Europe is of major conservation concern because rabbits are a key-stone species in natural ecosystems, the virus has been successfully used as a biological control of pest rabbits in Australia. However, rabbit numbers in Australia are currently rising again suggesting ongoing host adaptive changes. Accordingly, from both conservation and control perspectives it is important to know how rabbits are adapting and to work towards understanding the underlying genetic basis of this adaptation. Pathogenicity of a viral disease is not only influenced by the pathogen itself but likely also by the hostâ¿¿s immune gene expression which is poorly understood for wild animals. Here we used cDNA microarrays to obtain a general picture of the genetic pathways expressed in the liver during acute RHD infections in wild rabbits. We found that typical immune response pathways are activated during RHD but also identified differences in our results from those that might have been anticipated from laboratory studies. The down-regulation of cell surface protein genes in wild rabbits that avoided infection also suggests that the lower expression of certain surface proteins could confer protection from RHDV infection. This study expands our understanding of the molecular mechanisms at the host-pathogen interface during RHDV infection and pathogenesis and constitutes a step towards determination of genetic mechanisms that may eventually prove important in host-pathogen co-evolution under natural conditions.