The mammalian nucleus is arguably the most complex cellular organelle. It houses the vast majority of an organism's genetic material and is the site of all major genome regulatory processes. Reductionist approaches have been spectacularly successful at dissecting at the molecular level many of the key processes that occur within the nucleus, particularly gene expression. At the same time, the limitations of analyzing single nuclear processes in spatial and temporal isolation and the validity of generalizing observations of single gene loci are becoming evident. The next level of understanding of genome function is to integrate our knowledge of their sequences and the molecular mechanisms involved in nuclear processes with our insights into the spatial and temporal organization of the nucleus and to elucidate the interplay between protein and gene networks in regulatory circuits. To do so, catalogues of genomes and proteomes as well as a precise understanding of the behavior of molecules in living cells are required. Converging technological developments in genomics, proteomics, dynamics and computation are now leading towards such an integrated biological understanding of genome biology and nuclear function.