Genomic analyses have demonstrated that although less than 2% of the mammalian genome encodes proteins, at least two thirds is transcribed. Many nontranslated RNAs have now been characterized, and several long transcripts, ranging from 0.5 to over 100 kb, have been shown to regulate gene expression by modifying chromatin structure. Functions uncovered at a few well characterized loci demonstrate a wide diversity of mechanisms by which long noncoding RNAs can regulate chromatin over a single promoter, a gene cluster, or an entire chromosome, in order to activate or silence genes in cis or in trans. In reviewing the activities of these ncRNAs, we will look for common features in their interactions with the chromatin modifying machinery, and highlight new experimental approaches by which to address outstanding issues in ncRNA-dependent regulation of gene expression in development, disease and evolution.