Technetium-99m (99mTc) is currently, and will be in the foreseeable future, the most widely used radionuclide used in virtually all clinical diagnostic Nuclear Medicine laboratories in the world. Several 99mTc radiopharmaceuticals that are routinely used have become important factors in decisions on the diagnosis and treatment of patients with a variety of diseases. More sophisticated biological targeting vectors are being developed by the chemical and biomedical communities. The development of technologies and chelating agents for labeling these vectors with 99mTc, to produce diagnostic radiopharmaceuticals that have optimal in vivo specificities, will be essential for enhancement of the future of Nuclear Medicine in the health care arena worldwide. This chapter is focused primarily on a review of 99mTc complexes used for the formulation of currently approved radiopharmaceuticals, and highlights several chelation systems that are being used in the design of future 99mTc drugs. The chemical and structural properties of different 99mTc complexes and their relationships to their biolocalization and pharmacokinetic properties are described. Emphasis is placed on the importance of developing 99mTc complexes with a high degree of physicochemical flexibility, in order to optimize the pharmacological performance of future 99mTc-labeled drugs.