In the past two decades, our understanding of how the genome of mammalian cells is spatially organized in the three-dimensional (3D) space of the nucleus and how key nuclear processes are orchestrated in this space has drastically expanded. While genome organization has been extensively studied at the nanoscale, the higher-order arrangement of individual portions of the genome with respect to their intranuclear as well as reciprocal placement is less thoroughly characterized. Emerging evidence points to the existence of a complex radial arrangement of chromatin in the nucleus. However, what shapes this radial organization and whether it has any functional implications remain elusive. In this mini review, we first summarize our current knowledge on this rather overlooked aspect of mammalian genome organization. We then present a theoretical framework for explaining how the genome might be radially organized, focusing on the role of the guanine and cytosine density along the linear genome. Last, we discuss outstanding questions, hoping to inspire future experiments and spark interest in this topic within the 3D genome community.