The architecture of the cell nucleus has long been a matter of debate, and is still not completely understood yet. However, much progress has been made in the last few years, gradually unraveling nuclear infrastructure and its importance of the regulation of key genetic events. It is now established that the readout of genetic information and its faithful duplication are not only affected by regulatory sequences in the genome, but also by their localization in the threedimensional context and their relative position to functional subcompartments in the nucleus. Understanding how nuclear architecture and function are related and depend on each other has great potential to open up novel ways for the development of therapeutic agents. It is the purpose of this review to shed light on the role of nuclear architecture in regulating gene expression, and suggest that interfering with specific protein-protein interactions of transcription factors might provide new approaches to drug development.