The interaction between both beneficial and pathogenic microbes and their host has been the subject of many studies. Although the field of systems biology is rapidly evolving, the use of a systems biology approach by means of high-throughput techniques to study host–microbe interactions is just beginning to be explored. In this review, we discuss some of the most recently developed high-throughput ‘omics’ techniques and their use in the context of host–microbe interaction. Moreover, we highlight studies combining several techniques that are pioneering the integration of ‘omics’ data related to host–microbe interactions. Finally, we list the major challenges ahead for successful systems biology research on host–microbe interactions.