Enhancers play a major role in animal development by modulating spatiotemporal expression of genes. They interact with sequence-specific transcriptional regulators in response to internal and external cues to bring about transcriptional changes, thus serving as the critical link between an organism's genome and its phenotypic traits. Deciphering the biology of enhancers is a key to understanding the genetic basis of common human diseases. Although a large number of candidate enhancers have been annotated through genome-wide analyses of chromatin accessibility, transcription factor binding, and histone modification in diverse cell types, efforts to characterize their biological roles in human diseases have only begun. Recent experiments have suggested a role for the three-dimensional chromatin architecture in regulation of gene expression by enhancers.