The immune system is a complex network of cells and molecules protecting the host against pathogens in a delicately coordinated process. Resistance to disease is even more complicated as pathogens have their own set of genes that interact with the host immune system in any given environment. To reduce the complexity, the host-pathogen interaction can be investigated at the cellular level in an in vitro setting. Utilizing this concept to study the cells of the immune system in the face of pathogenic challenge is a useful approach to examine the genetics of disease resistance. Therefore, using cellular immuno-genomics methods, two bactericidal responses of bovine monocyte-derived macrophages (MDMs), namely oxidative burst and phagocytosis, against Escherichia coli (E. coli), Staphylococcus aureus were investigated. This study revealed that oxidative burst is strongly associated with host genetics with a heritability of approximately 0.8. Six Holstein cows that had been classified as high and low NO- responders were then selected to determine the overall transcriptomic profile of their MDMs. Results showed two clusters of inflammatory- and hypoxia-related transcription factors (TF), including three pioneering TFs (AP1, PU.1, IRF4 and IRF1), that are genetically controlled in cattle. This study uncovered the mechanisms that lead to distinct proinflammatory profiles among macrophages and that these are controlled by natural genetic polymorphisms in an outbred population. Finally, a genome-wide association study was performed to identify the loci that are associated with the magnitude of the oxidative burst response in macrophages. Sixty SNPs across 22 chromosomes of the bovine genome were identified to be significantly associated with NO- production of MDM. Functional genomic analysis showed a significant interaction between genes that are nearby significant SNPs and mitochondria-related differentially expressed genes from the transcriptomic study. In conclusion, the results of the current study suggest that the genetic regulation of response to hypoxia is the critical step that shapes the proinflammatory response of bovine MDM. Since all cells in one individual carry the same alleles, the effect of genetic predisposition of sensitivity to hypoxia will likely be notable on the clinical outcome to a broad range of host-pathogen interactions.