Chromatin is compartmentalized into ‘active’ and ‘inactive’ domains that reflect the transcriptional potential of the genomic regions that segregate into them. The higher-order assemblies of chromatin also contribute towards stringent and signal-dependent regulation of gene activity. The global chromatin organizer SATB1 has emerged as a key factor integrating higher-order chromatin architecture with gene regulation. Studies in recent years have unraveled the role of SATB1 in organization of chromatin ‘loopscape’ and its dynamic nature in response to physiological stimuli. At genome-wide level, SATB1 seems to play a role in organization of the transcriptionally poised chromatin. Our recent studies established SATB1 as a mediator of Wnt/?-catenin signaling and provided mechanistic insights into how two factors with contrasting activities, namely CtBP1 and ?-catenin, cooperate with the chromatin organizer SATB1 to regulate gene expression upon Wnt signaling. In conjunction with various histone modifiers, SATB1 orchestrates gene expression profiles during development and differentiation of multiple cell types. The implications of these findings towards development and differentiation of the cells of the immune system and towards diseases such as cancer will be discussed.