Developmental and tissue-specific expression of higher eukaryotic genes involves activation of transcription at the appropriate time and place and keeping it silent otherwise. Unlike housekeeping genes, tissue-specific genes generally do not cluster on the chromosomes. They can be found in gene-dense regions of chromosomes as well as in regions of repressive chromatin. Depending on the location, shielding against positive or negative regulatory effects from neighboring chromatin may be required and hence insulator and boundary models were proposed. They postulate that chromosomes are partitioned into physically distinct expression domains, each containing a gene or gene cluster with its cis-regulatory elements. Specialized elements at the borders of such domains are proposed to prevent cross-talk between domains, and thus to be crucial in establishing independent expression domains. However, genes and associated cis-acting sequences often do not occupy physically distinct domains on the chromosomes. Rather, genes can overlap and cis-acting sequences can be found tens or hundreds of kilobases away from the target gene, sometimes with unrelated genes in between. Therefore the ability of a gene to communicate with positive cis-regulatory elements rather than the presence of specialized boundary elements appears to be key to establishing an independent expression profile. Our recent finding that active β-globin genes physically interact in the nuclear space with multiple cis-regulatory elements, with inactive genes looping out, has provided a potential mechanistic framework for this model. We refer to such a spatial unit of regulatory DNA elements as an active chromatin hub (ACH). We propose that productive ACH formation underlies correct gene expression, requiring the presence of protein factors with the appropriate affinities for each other bound to their cognate DNA sequences. Proximity and specificity determines which cis-acting sequences and promoter(s) form an ACH, and thus which gene will be expressed. Other regulatory sequences can interfere with transcription by blocking the appropriate physical interaction between an enhancer and promoter in the ACH. Possible mechanisms by which distal DNA elements encounter each other in the 3D nuclear space will be discussed.