Enhancers are distally located genomic cis -regulatory elements that integrate spatiotemporal cues to coordinate gene expression in a tissue-specific manner during metazoan development. Enhancer function depends on a combination of bound transcription factors and cofactors that regulate local chromatin structure, as well as on the topological interactions that are necessary for their activity. Numerous genome-wide studies concur that the vast majority of disease-associated variations occur within non-coding genomic sequences, in other words the ‘ cis -regulome’, and this underscores their relevance for human health. Advances in DNA sequencing and genome-editing technologies have dramatically expanded our ability to identify enhancers and investigate their properties in vivo , revealing an extraordinary level of interconnectivity underlying cis -regulatory networks. We discuss here these recently developed methodologies, as well as emerging trends and remaining questions in the field of enhancer biology, and how perturbation of enhancer activities/functions results in enhanceropathies. [ABSTRACT FROM AUTHOR]