Nuclear factor of activated T cells (NFAT) plays a central role in activating gene expression at the level of chromatin structure. A study now reveals that NFAT may also help to organize chromatin domains and enable enhancer-promoter communication. In activated T cells, inducible intrachromosomal looping occurs between the tumor necrosis factor-alpha (TNF-alpha) gene promoter and two NFAT-dependent enhancers located at -9 kb and +3 kb. This topology places the TNF-alpha gene and the adjacent lymphotoxin (LT) genes in separate loops, thereby allowing independent regulation of the TNF-alpha gene within a multigene locus. These findings build on other studies that indicate that NFAT is intimately associated with activities that disrupt nucleosomes within enhancers and mobilize nucleosomes across extensive chromatin domains linking enhancers and promoters. Taken together, these studies highlight NFAT as a factor that creates a chromatin environment that is permissive for both the recruitment and the clustering of factors that control transcription at promoters and enhancers.