The differentiation of pluripotent or totipotent cells into various differentiated cell types is accompanied by a restriction of gene expression patterns, alteration in histone and DNA methylation, and changes in the gross nuclear organization of eu- and heterochromatic domains. Several recent studies have coupled genome-wide mapping of histone modifications with changes in gene expression. Other studies have examined changes in the subnuclear positioning of tissue-specific genes upon transcriptional induction or repression. Here we summarize intriguing correlations of the three phenomena, which suggest that in some cases causal relationships may exist.