This chapter covers production of radionuclides referred to as nuclear activation or radioactivation. With respect to their origin, radioactive nuclides (radionuclides) are divided into two categories: naturally occurring and man-made or artificially produced. Three models of neutron activation in a nuclear reactor are discussed in this chapter and examples relevant to medical physics are given for each model. The three models are: saturation model based on infinite number of parent nuclei; depletion model based on finite number of parent nuclei; and depletion-activation model based on depletion of parent nuclei and activation of daughter nuclei. The chapter also presents a discussion of two nuclear chain reactions: fission and fusion and the production of the technetium-99m radionuclide with a molybdenum–technetium radionuclide generator. The chapter concludes with a discussion of proton activation with protons obtained from a cyclotron.