Post-genome era experimental strategies seek to understand cellular pathways globally rather than through examination of individual components. Genomics and proteomics provide the experimental tools to establish the framework of gene and protein pathways present in a cell. These methods are complemented by emerging in vivo microscopy approaches, which permit placement of pathways within the architectural context of the cell. Analysis of dynamic live cell microscopy data combined with computational analyses finally allows the quantitative, mechanistic description of protein properties and pathways operating in living cells. Here we discuss how genomics and proteomics are changing the study of the cell nucleus and how in vivo microscopy methods have contributed to our changing conceptual and mechanistic understanding of nuclear architecture and function. Mapping of gene loci and genome regions are beginning to reveal organizational principles of the genome within the cell nucleus, proteomic analysis of subnuclear compartments and the gene expression machinery is providing insights into the molecular nature of nuclear events, and in vivo microscopy is illuminating the dynamic nature of nuclear organization. Initial findings from these efforts make clear that nuclear and cellular behavior can not be described by linear pathways. New tools such as computational modeling are providing evidence that emerging concepts such as network organizations and stochastic interactions are crucially important for cellular function and organization. These insights are changing our view of the nucleus and the cell as a whole.