Transcription activation of a gene involves the ordered recruitment of components of the basal transcription machinery in concert with alterations in chromatin structure, including nucleosome remodeling and posttranslational modification of histones. Enhancers and locus control regions (LCRs) that are remote from the genes they activate, recruit the complexes that carry out these alterations and, sometimes, recruit RNA polymerase II. The question of how these distant activators interact with their target genes has been of long-standing interest. Recent data indicate that LCRs mediate contact with their coordinate genes through the formation of domains of histone modification and of intra- and inter-chromosomal loops and that they might localize genes within nuclear regions that favor transcription.