The mammalian immune system is capable of detecting and responding to different infectious conditions with specificity at the adaptive level, however whether this ability extends to individual cells of the innate immune system is unclear. The hypothesis of this thesis is that macrophages, as individual cells, can distinguish between productive and non-productive virus infections and respond differently at the gene expression and secreted protein level. To test the hypothesis, mouse bone marrow derived macrophages (BMDMs) were infected in parallel with either a productive (live) and non-productive (attenuated) strain of murine cytomegalovirus (MCMV) and profiled temporally using a range of techniques. Both productive and non-productive MCMV infection resulted in strong type I IFN induction in BMDMs, however induction was significantly more rapid in response to productive infection. In addition, chemoattractant and pro-inflammatory cytokines TNFα, IL-6, RANTES, MIG and MIP-2 were secreted to significantly higher levels in response to productive MCMV infection, and curtailed in response to non-productive MCMV infection. Furthermore, genome-wide microarray profiling revealed a number of co-expressed gene networks regulated differentially in response to the two conditions. This consisted of macrophage gene networks targeted for modulation by de novo MCMV proteins, and late macrophage response genes regulated specifically in response to productive MCMV infection. To further explore the mechanisms of transcriptional regulation during macrophage antiviral response, BMDMs from mice lacking either the type I IFN receptor (Ifnar1) or the IFNβ (Ifnb1) gene were profiled using a similar approach. The resulting genome-wide transcriptional data provided a unique insight into the relationship between type I IFN regulation and the macrophage transcriptome in response to MCMV infection. Overall, the study utilizes a combination of genetic mutants from both host and pathogen to investigate mechanisms of virus detection and host transcriptional regulation during the innate immune response to MCMV infection in macrophages.