CCCTC-binding factor (CTCF) plays indispensable roles in transcriptional inhibition/activation, insulation, gene imprinting, and regulation of 3Dchromatin structure. CTCF contributes to formation of genome multi-dimensions, regulation of dimensional changes, or control of central signals to transcriptional networks. A large number of factors affect CTCF binding, methylation/demethylation, base mutation, or poly(adp-ribosyl)ation. CTCF is one of the most important elements in the regulation of chromatin folding by combining with CBSs in TADs in a positive-reverse or reverse-positive orders. CTCF acts as a versatile nuclear factor, a transcriptional activator or repressor, an insulator binding factor, or a regulator of genomic imprinting as required for various biological procedures. Although molecular regulatory mechanisms of CTCF in cell differentiation and disease development remains unclear, roles of CTCF in carcinogenesis have been intensively explored. There is little understanding about regulatory roles of CTCF in inflammation-associated transcriptional signaling, cell injury, organ dysfunction, and systemic responses. It is also highly expected that further in-depth studies of CTCF control mechanisms can provide better understanding of disease development and potential disease-specific biomarkers and therapeutic targets.