It is known anecdotally among medicinal chemists that small chemical modifications occasionally, in puzzling ways can turn antagonists into agonists – and the other way around. We have studied this phenomenon in a systematic manner using a multitude of terminally modified wFw tripeptides in combination with a large library of mutants of the constitutively active ghrelin receptor. Efficacy –switch epitopes was identified in the ligand, where certain types of chemical changes swapped the ligand between high potency agonism and equally high potency inverse agonism. The wFw-containing peptides – agonists as well as inverse agonists – are affected by receptor mutations covering the whole main ligand-binding pocket with key interaction sites being an aromatic cluster in TM-VI and VII and residues on the opposing face of TM-III. Importantly, gain-of-function in respect of either increased agonist or increased inverse agonist potency or in respect of swap (up and down) between high potency versions of these properties, was obtained at a number of key positions. In particular, space generating substitutions at position III:04 shifted the efficacy of this chemotype ligands from inverse agonism toward agonism, whereas similar substitutions at position III:08 – one helical turn below – shifted the efficacy from agonism toward inverse agonism. It is suggested that the relative position of the ligand in the binding pocket between this “efficacy shift region” on TM-III and the opposing aromatic cluster in TM-VI and TM-VII leads either to agonism – i.e. in a superficial binding mode – or it leads to inverse agonism – i.e. in a more profound binding mode. This relationship between different binding modes and opposite efficacy is in accordance with the Global Toggle Switch Model for 7TM receptor activation (Annu.Rev.Pharmacol.Toxicol. (2006) 46: 481-519). Thus, it is clear that efficacy can be structurally “uncoupled” from affinity / potency and a picture of the structural basis for this is emerging which fits with efficacy-swap mutations in for example the CB1 and opioid system.