Developments in chromosome conformation capture (3C) technologies have revealed that the three-dimensional organization of a genome leads widely separated functional elements to reside in close proximity. However, the mechanisms responsible for mediating long-range interactions are still not completely known. In this review, we firstly evaluate and compare the current seven 3C-based methods, summarize their advantages and discuss their limitations to our current understanding of genome structure. Then, software packages available to perform the analysis of 3C-based data are described. Moreover, we review the insights into the two main mechanisms of long-range interactions, which regulate gene expression by bringing together promoters and distal regulatory elements and by creating structural domains that contain functionally related genes with similar expression landscape. At last, we summarize what is known about the mediating factors involved in stimulation/repression of long-range interactions, such as transcription factors and noncoding RNAs.