The first mentioning of the word “receptor” for the structure with which a bioactive compound should react for obtaining its specific influence on a physiological system goes back to the years around 1900. The receptor concept was adapted from the lock and key theory for the enzyme substrate and blockers interactions. Through the years the concept, in the beginning rather being a metaphor, not a model, was refined and became reality in recent years. Not only the structures of receptors were elucidated, also the receptor machineries were unraveled. Following a brief historical review we will describe how the recent breakthroughs in the experimental determination of G protein-coupled receptor (GPCR) crystal structures can be complemented by computational modeling, medicinal chemistry, biochemical, and molecular pharmacological studies to obtain new insights into the molecular determinants of GPCR–ligand binding and activation. We will furthermore discuss how this information can be used for structure-based discovery of novel GPCR ligands that bind specific (allosteric) binding sites with desired effects on GPCR functional activity.