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Recent advances in chromosome conformation capture technologies are improving the current appreciation of how 3D genome architecture affects its function in different cell types and disease. Long-range chromatin interactions are organized into topologically associated domains, which are known to play a role in constraining gene expression patterns. However, in cancer cells there are alterations in the 3D genome structure, which impacts on gene regulation. Disruption of topologically associated domains architecture can result in alterations in chromatin interactions that bring new regulatory elements and genes together, leading to altered expression of oncogenes and tumor suppressor genes. Here, we discuss the impact of genetic and epigenetic changes in cancer and how this affects the spatial organization of chromatin. Understanding how disruptions to the 3D architecture contribute to the cancer genome will provide novel insights into the principles of epigenetic gene regulation in cancer and mechanisms responsible for cancer associated mutations and rearrangements.