Pathogenic microorganisms exploit host metabolism for sustained survival by rewiring its metabolic interactions. Therefore, several metabolic changes are induced in both pathogen and host cells in the course of infection. A systems-based approach to elucidate those changes includes the integrative use of genome-scale metabolic networks and molecular omics data, with the overall goal of better characterizing infection mechanisms for novel treatment strategies. This review focuses on novel aspects of metabolism-oriented systems-based investigation of pathogen-human interactions. The reviewed approaches are the generation of dual-omics data for the characterization of metabolic signatures of pathogen-host interactions, the reconstruction of pathogen-host integrated genome-scale metabolic networks, which has a high potential to be applied to pathogen-gut microbiota interactions, and the structure-based analysis of enzymes playing role in those interactions. The integrative use of those approaches will pave the way for the identification of novel biomarkers and drug targets for the prediction and prevention of infectious diseases.