AbstractEnhancers are short segments of regulatory DNA that control when and in which cell‐type genes should be turned on in response to a variety of extrinsic and intrinsic signals. At the molecular level, enhancers serve as a genomic scaffold that recruits sequence‐specific transcription factors and co‐activators to facilitate transcription from linked promoters. However, it remains largely unclear how enhancers communicate with appropriate target promoters in the context of higher‐order genome topology. In this review, we discuss recent progress in our understanding of the functional interplay between enhancers, genome topology, and the molecular properties of transcription machineries in gene regulation. We suggest that the activities of transcription hubs are highly regulated through the dynamic rearrangement of enhancer‐promoter and promoter‐promoter connectivity during animal development.