The functional output of the genome is closely dependent on its organization within the nucleus, which ranges from the 10-nm chromatin fiber to the three-dimensional arrangement of this fiber in the nuclear space. Recent observations suggest that intra- and inter-chromosomal interactions between distant sequences underlie several aspects of transcription regulatory processes. These contacts can bring enhancers close to their target genes or prevent inappropriate interactions between regulatory sequences via insulators. In addition, intra- and inter-chromosomal interactions can bring co-activated or co-repressed genes to the same nuclear location. Recent technological advances have made it possible to map long-range cis and trans interactions at relatively high resolution. This information is being used to develop three-dimensional maps of the arrangement of the genome in the nucleus and to understand causal relationships between nuclear structure and function.