The project nano-WAC aims to develop a new miniaturized affinity chromatography-based technology (nano-WAC) that will enable the innovative ligand-screening against native membrane proteins (MPs), notably G protein–coupled receptors (GPCRs), a large family of MPs with a tremendous clinical potential. To date, no robust biophysical technique is available for the discovery of small ligands (fragments) targeting MPs that are available in minute amounts. Our strategy, based on the combination of the separation/detection powers of affinity chromatography and mass spectrometry (nano-WAC-MS), will open the way to the screening of fragment library for the identification of weak affinity fragments in the context of the Fragment Based Drug Discovery approach. After development with one prototypical GPCR, this assay will be extended to the ghrelin receptor GHSR that is a prominent target in biomedicine.