© 2014 John Wiley & Sons, Ltd. All rights reserved. There are an abundant number of metal radionuclides applicable for use in nuclear medicine, and metal radionuclides are currently used in the majority of nuclear medicine procedures. The utility of metal-based agents or radiopharmaceuticals is dependent on ligand design to yield stable coordination complexes with the appropriate functionality. Fundamental coordination chemistry of the various metals acts as a base for ligand design. But radiopharmaceutical development requires special consideration in many aspects of ligand design, from the ligand's impact on coordination reaction conditions and kinetics to the physiological fate of the resulting complex. This chapter explores in general the numerous features of ligand design for metal-based radiopharmaceutical development. As well, this chapter delves into the specific considerations for particular radionuclides that are of interest to the field of nuclear medicine.