Rational refinement and development of receptor-active ligands can come from high-resolution insights into the structures of these potential drug targets. Structural insights for Family A G protein-coupled receptors (GPCRs) have been advanced substantially with the recently reported crystal structure of the intact β2-adrenergic receptor. While high-resolution structural insights for Family B GPCRs are also advancing, this is currently limited to the functionally important extracellular amino-terminal tail domain of those receptors. The current report describes how these structures can provide leads for the development of small-molecule agonist drugs acting at Family B GPCRs. Endogenous agonist activity within the amino terminus of these receptors could be key for the development of such drugs.