A typical animal cell contains a meter of DNA packaged into nucleus whose diameter is ten thousand times smaller. Though the packaging organization of DNA has many important consequences for gene expression and cell behavior, we currently have only a limited understanding of its organization in the interphase nucleus. How packaging shapes or is shaped by genome activity such as transcription or repression is also poorly understood. I will present a new imaging approach to visualize the three-dimensional organization of regulatory regions of the genome in intact cells using super-resolution microscopy. I will show that domains of DNA with distinct functional properties have clearly distinct packaging organization and that their packaging densities characterized by distinct power-law scaling relations. These differences in packaging have immediate implications for understanding the control of gene expression, which I will discuss. To quantify such changes in gene expression at the systems level, we developed a second method, multiplexed error-robust fluorescent in situ hybridization (MERFISH) – for uniquely labeling single RNA particles from as many as 1000 distinct RNA species in a single cell. The ability to quantify the abundance and spatial organization of RNAs at the transcriptome scale with this technology enables precise characterization of cell types and can provide a detailed link between gene regulation and expression. I will discuss applications of this technology to elucidating new patterns of sub-cellular organization of RNA and identifying novel gene interactions by measuring transcriptional noise.