Differentiation of specific cell types during the development of mammals requires the selective silencing or activation of tissue-specific genes. Locus control regions (LCRs) are gene regulatory elements that act in cis to ensure that active transcriptional units are established in all cells of a given cell lineage. Over the past year, it has become clear that this process takes place at the level of chromatin remodelling, and that LCRs ensure that this decision is made by both alleles in every cell. Studies on LCRs and analysis of gene expression in transgenic mice at the single cell level has revealed that the breakdown in LCR function accompanying the deletion of specific sequences results in a phenomenon known as position effect variegation, described in detail in yeast and Drosophila. Thus, when located in close proximity to heterochromatin a transgene linked to a disabled LCR is randomly silenced in a proportion of cells. This finding implies that all subregions within an LCR are necessary to ensure the establishment of an open chromatin configuration of a gene even when the latter is located in a highly heterochromatic region.