Membrane proteins pose problems for the application of NMR‐based ligand‐screening methods because of the need to maintain the proteins in a membrane mimetic environment such as detergent micelles: they add to the molecular weight of the protein, increase the viscosity of the solution, interact with ligands non‐specifically, overlap with protein signals, modulate protein dynamics and conformational exchange and compromise sensitivity by adding highly intense background signals. In this article, we discuss the special considerations arising from these problems when conducting NMR‐based ligand‐binding studies with membrane proteins. While the use of 13C and 15N isotopes is becoming increasingly feasible, 19F and 1H NMR‐based approaches are currently the most widely explored. By using suitable NMR parameter selection schemes independent of or exploiting the presence of detergent, 1H‐based approaches require least effort in sample preparation because of the high sensitivity and natural abundance of 1H in both, ligand and protein. On the other hand, the 19F nucleus provides an ideal NMR probe because of its similarly high sensitivity to that of 1H and the lack of natural 19F background in biologic systems. Despite its potential, the use of NMR spectroscopy is highly underdeveloped in the area of drug discovery for membrane proteins.