Exciting advances in recent years have led to an increased appreciation of genome-wide chromatin organization and its association with transcriptional programs. One of the major findings has been the identification of regions along a chromosome that interact to create topologically associated domains (TADs). These structures are thought to be evolutionarily conserved even when the genes within the TAD are altered in transcriptional activity. However, it is currently unclear how chromatin is organized in functionally distinct cells within the same individual. The immune system represents an excellent model to test these questions, with a number of different immune cell lineages arising from a common hematopoietic stem cell. We have produced high-resolution genome-wide HiC contact maps from both mouse and human and used our bioinformatics package (diffHiC) to show that different primary immune cell lineages have very distinct global chromatin organization. Using this dataset we were also able to reveal a multitude of novel long-range lineage-specific interactions that linked distant enhancers to promoters and that fit the description of TADs. However the absence of these structures in other immune populations suggests that the TADs may not be as conserved as first thought. Overall our data show that chromatin domains can be dramatically altered in structure to support lineage-specific gene expression programs.