With the advent of advances in chemical and molecular biology, the structure of parathyroid hormone (PTH); the related protein, parathyroid-related protein (PTHrP); and their principal receptor (PTH/PTHrP receptor [PTHR1]) were established over recent decades. Tests with purified hormonal peptide in humans led to the surprising, even paradoxical, finding that PTH can be used pharmacologically to build bone, providing a dramatic therapeutic impact on osteoporosis. These developments plus recent insights into previously unappreciated ligand-receptor conformations that cause prolonged biological activation have stimulated the field of calcium and bone biology and posed new questions about the role of PTH and PTHrP as well as possible new directions in the therapy of osteoporosis and calcium-deficit states.