Terrorism involving nuclear or radiological weapons can devastate populations, city infrastructures, and entire sociopolitical systems. In our age of nuclear medicine and therapeutic radiation delivery, the unauthorized and illegal acquisition of radioactive materials needed for such an attack is always a possibility and risk. Physicians handling high-energy isotopes for medical radiotherapy must be aware of the basic security requirements as outlined by the Nuclear Regulation Commission, which include background checks and authorized access, physical protection during radionuclide use, and physical protection during its transit. Special discussion is given to the Leksell Gamma Knife and its Category 1 cobalt-60 radioactive source due to its significant potential for deployment in a weaponized device. Although this article presents a perspective relating to American rules and regulations, these precautions are applicable anywhere similar situations exist. Understanding these materials and the security they require is essential to preventing the disastrous outcomes should these isotopes fall into terrorist use.