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Radioactive isotopes have underpinned radiation medicine and research since their discovery. From early interstitial applications of radium and 137Cs to modern application of 192Ir after-loaders and 125I seeds in brachytherapy, radioisotopes remain the standard of care for several prostate, gynecologic, and head and neck malignancies. However, the continuous emission and high specific activity of sealed sources impose substantial logistical, regulatory, and security burdens. International regulatory agencies therefore advocate minimizing reliance on high-activity sources where feasible. Advances in image-guided, energy-concentrating modalities have yielded clinically mature platforms capable of delivering ablative energy with steep dose gradients and normal-tissue sparing without the need for radioactivity. This review surveys five such modalities: (1) laser interstitial thermal therapy, an MR-thermography-guided laser ablation system; (2) intraoperative radiation therapy, using low-kV x rays or electrons; (3) MRI-guided linear accelerators (MR-LINAC); (4) ultra-high dose rate "FLASH" external-beam therapy; and (5) particle therapy using protons and heavy ions. Collectively, these technologies promise non-radioactive, highly conformal treatment options that leverage diverse radiobiological mechanisms to redefine therapeutic ratios in clinical practice.