A transformation in the structural biology of membrane-associated receptors, particularly of G Protein-Coupled Receptors (GPCRs), has occurred over the last 10 years and continues to build momentum today. Remarkable new protein–ligand X-ray crystal and latterly cryo-EM structures have been published giving a detailed appreciation of how molecules bind to a plethora of fascinating binding sites. The profound impact of these new data on design of ligands for drug discovery, a detailed consideration of the consequences to the computational chemistry community, and a description of some representative applications of Structure-Based Drug Design (SBDD) are described in this article, with a focus on GPCRs.