Recent advances in our understanding of how the genome is folded within the nucleus have included cases in which this positioning correlates with gene expression, either positively or negatively. But is the 3-D location of a gene a cause or an effect of its expression? In this Perspective I articulate the problem and then cite as guideposts recent cases where causation has indeed been arguably established. The hope is to critically illuminate this issue for continued consideration in this important, evolving field.