More than 2000 variations are described within theCFTR(Cystic Fibrosis Transmembrane Regulator) gene and related to large clinical issues from cystic fibrosis to mono-organ diseases. Although theseCFTR-associated diseases have been well documented, a large phenotype spectrum is observed and correlations between phenotypes and genotypes are still not well established. To address this issue, we present several regulatory elements that can modulateCFTRgene expression in a tissue-specific manner. Among them,cis-regulatory elements act through chromatin loopings and take part in three-dimensional structured organization. With tissue-specific transcription factors, they form chromatin modules and can regulate gene expression. Alterations of specific regulations can impact and modulate disease expressions. Understanding all those mechanisms highlights the need to expand research outside the gene to enhance our knowledge.