[en] While animal models remain essential for inferring causality, they exhibit important limitations, which restrict the direct translation of findings into new approaches aimed at steering host–microbe interactions for the improvement of human health. Different in vitro models have therefore been developed which incorporate human cell types and microbiota. By virtue of their intricate designs, these models result in human and microbial read-outs reflective of in vivo gut physiology, and present important alternatives to animal models. However, to allow systematic investigations of the interactions between gut microbiota and different human cell types and body systems, ever more complex cell assemblies are necessary which will culminate in the establishment of personalized in vitro models. Such models will allow the unravelling of human–microbe interdependencies and will open exciting new avenues for microbiome-tailored nutrition and drug development.