Recent methodology, to be described, now makes possible specific localization and analysis of genetic loci within 3-Dimensional interphase nuclei in intact cells and tissues with minimal perturbation of the chromosome structure (Dernburg and Sedat, 1997). These techniques define genetic loci that specifically interact with the nuclear envelope and interior structures; we are able to map all loci to highly localized 3-dimensional positions within Drosophila embryonic nuclei (Marshall et al, 1996). S-Dimensions-as-a-function-of-time (4-D) studies of live nuclei, from Yeast and Drosophila, allow dynamic chromosome interactions to be probed and quantitated. Our results suggest a very dynamic but highly determined and organized nucleus. Using these approaches, we can now study specific mechanisms leading to homologue chromosome pairing and position-effect variegation (Dernburg et al., 1996).