In this study we have used Clostridium perfringens infections of mice as a model for myonecrotic clostridial infections. To examine host-pathogen interactions at the molecular level RNA-seq analysis of the transcriptomes of both the pathogen and the host was carried out. Comparison of the bacterial gene expression profile obtained from muscle tissue 90 mins after infection with that from the equivalent in vitro culture showed that 916 genes (32%) were differentially expressed in vivo. Genes that were up-regulated in the muscle tissue included at least nine potential virulence genes and several metabolic genes, but unexpectedly did not include the major toxin genes. Comparison of the murine transcriptome from the infected muscle tissues to that from the equivalent tissues of mock-infected mice revealed that 261 host genes were up-regulated in a C. perfringens infection. Bioinformatics analysis revealed that these genes included genes encoding TLR and NLR signalling components and genes involved in cytokine and chemokine production. The data provided evidence that TLR2 and NLRP3 inflammasome signalling was activated in C. perfringens-infected muscle tissue. These studies represent the first successful transcriptional profiling of both bacterial and host genes during an active C. perfringens infection. They have led to the identification of bacterial genes that may be involved in the disease process and host genes that are activated in response to this infection, thereby providing novel insights into host-pathogen interactions in these often fatal infections.