The spatial organization of the genome is essential for the precise control of gene expression. Recent advances in sequencing and imaging technologies allow us to explore the 3D genome and its relationship to gene regulation at an unprecedented scale. In this review, we provide an overview of lessons learned from studying the chromatin structure and their implications in communications between gene promoters and distal cis-regulatory elements, such as enhancers. We first review the current knowledge of general genome organization, followed by the importance of chromatin folding in gene regulation. Next, we proceed to a brief survey of the recently developed chromosome conformation capture technologies, as well as most widely adopted read-outs from such data. We then introduce two emerging models that offer explanations regarding how distal enhancers achieve transcriptional control of target genes in the 3D genome. Last, we discuss the promising prospects of leveraging knowledge in chromatin spatial organization for studying complex diseases and traits.