Recent evidence suggests that dynamic three-dimensional genomic interactions in the nucleus exert critical roles in regulated gene expression. Here, we review a series of recent paradigm-shifting experiments that highlight the existence of specific gene networks within the self-organizing space of the nucleus. These gene networks, evidenced by long-range intrachromosomal and interchromosomal interactions, can be considered as the cause or consequence of regulatory biological programs. Changes in nuclear architecture are a hallmark of laminopathies and likely potentiate genome rearrangements critical for tumor progression, in addition to potential vital contribution of noncoding RNAs and DNA repeats. It is virtually certain that we will witness an ever-increasing rate of discoveries that uncover new roles of nuclear architecture in transcription, DNA damage/repair, aging, and disease.