We have used a combination of light and electron microscopy, including live-cell imaging, together with engineering tagged chromosome regions, to provide insights into chromosome and nuclear organization in eukaryotic cells. Most recently we have developed a novel genomic method to predict the location of chromosomes, genome-wide, relative to different nuclear compartments. I will describe several examples from this work addressing how DNA replication and transcription may occur on a highly condensed chromosome template, demonstrating long-range directional movements of chromosomes over several microns at velocities of ~ 1 micron/min towards specific nuclear compartments, and demonstrating the subsequent transcriptional amplification of certain genes when they are brought into contact with certain nuclear compartments- specifically nuclear speckles. Genome-wide analysis reveals that these nuclear speckles act as a hub for roughly half of the gene-dense transcriptional "hot-zones" in human chromosomes. More generally, comparing different cell lines suggests a tight correlation between small shifts in nuclear position with changes in gene expression, the logic of which remains unclear. Together our work suggests that both large-scale chromatin compaction and the active positioning of chromosome regions within the nucleus act to modulate levels of transcription.