Proper regulation of gene expression is essential for cell function, and dysregulation of gene expression is a primary cause of disease. The primary units of gene control in humans are enhancers. Enhancers can be located far away from the genes they control on the linear genome, raising the question of how the cell ensures that the right enhancer contacts and activates the right gene. We will present new super-resolution live-cell imaging and 3D genomics methods we have developed to begin to answer this question, what we have learned from these studies, and how we are beginning to use these technologies to translate findings from human genetics into a better understanding of how 3D genome misfolding causes disease.