The human gut microbiota performs essential functions for host and well‐being, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and tissue metabolomes are greatly influenced by the microbiota, with many health‐relevant metabolites being considered ‘mammalian–microbial co‐metabolites’. To systematically investigate this complex host–microbial co‐metabolism, a systems biology approach integrating high‐throughput data and computational network models is required. Here, we review established top‐down and bottom‐up systems biology approaches that have successfully elucidated relationships between gut microbiota‐derived metabolites and host health and disease. We focus particularly on the constraint‐based modeling and analysis approach, which enables the prediction of mechanisms behind metabolic host–microbe interactions on the molecular level. We illustrate that constraint‐based models are a useful tool for the contextualization of metabolomic measurements and can further our insight into host–microbe interactions, yielding, e.g., in potential novel drugs and biomarkers. WIREs Syst Biol Med 2015, 7:195–219. doi: 10.1002/wsbm.1301This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Metabolism Laboratory Methods and Technologies > Metabolomics