Over the last decades it became clear that mammalian nuclei are highly organized. Nuclear processes like DNA replication and RNA metabolism take place in distinct subnuclear foci, which are enriched for enzymes involved in the corresponding biochemical reactions. This colocalization of functions with their respective factors is often referred to as functional organization of the nucleus. This organization is achieved by assembly of different enzymes and regulatory factors into high-molecular-weight complexes that are tethered to insoluble nuclear structures. Recently, several links between nuclear structure, gene expression, DNA replication, and methylation have been described that illustrate the interrelation of higher-order structures and nuclear functions. New insights into the functional organization of the nucleus and how it could explain the high precision and overall coordination of nuclear processes are discussed.