Significant efforts have been made to identify and validate oncoproteins and non-coding RNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements (NCREs), which orchestrate the three-dimensional organization of the genome (3D genome) and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts to decipher the noncoding cis-regulatory code and performing systematic surveys of functional NCREs and recurrent 3D genome alterations in both cancerous and non-malignant cells within tumor tissues will pave the way to development of novel therapeutic strategies. （A commentary which will be published in Cancer Discovery on 1^st November 2024）