Staphylococcus aureus is a common human commensal bacterium. However, these colonising bacteria can invade the bloodstream, causing devastating infections, aggravated by the widespread emergence of resistance to last-line antibiotics like vancomycin. Understanding how S. aureus infection occurs has become increasingly challenging. In this study, we integrated multi-omics data including transcriptomics, proteomics, and metabolomics to identify the molecular signatures of S. aureustransition into human serum. We focus on five sepsis isolates representing the most common lineages of S. aureus that are clinically important in Australia. Our preliminary results show that distinct S. aureus isolates share common and strain-specific responses to human serum. Interestingly, the up-regulation of genes involved in iron acquisition pathways was conserved across S. aureus lineages. We observed that staphylobilin-forming heme oxygenase (isdI) was up-regulated, at both transcriptional and translational levels, in S. aureus exposed to human serum. Consistent with our analyses, an isogenic isdI mutant showed growth defects in human serum when compared to S. aureus wild-type JE2, suggesting the importance of iron uptake for bacterial survival in human serum. For future analyses, multivariate data integration will be used to identify new potential conserved and strain-specific targets for further therapeutic treatments of sepsis.