The f-block elements, which comprise both the lanthanide and actinide series, possess interesting spectroscopic, magnetic, and nuclear properties that make them uniquely suited for a range of biomedical applications. In this Forum Article, we provide a concise overview on the different ways that these elements are employed in medicine, highlighting their dual implementation in both diagnostic and therapeutic applications. A key requirement for the use of these labile metal ions in medicine is a suitable chelating agent that controls their in vivo biodistribution. Toward this goal, we also report our research describing the synthesis and characterization of a rigid 18-membered macrocycle called CHX-macropa, an analogue of the previously reported nonrigid ligand macropa (J. Am. Chem. Soc. 2009, 131, 3331). The lanthanide coordination chemistry of CHX-macropa is explored in detail by pH potentiometry and density functional theory (DFT) calculations. These studies reveal that CHX-macropa exhibits an enhanced thermodynamic selectivity for large over small lanthanides in comparison to its nonrigid analogue macropa. DFT calculations suggest that a key factor in the enhanced selectivity of this ligand for the large f-block ions is its rigid macrocyclic core, which cannot adequately distort to interact effectively with small ions. On the basis of its high affinity for large f-block ions, the design strategies implemented in CHX-macropa may be valuable for applying these elements in the diagnosis or treatment of disease.