The three pillars of rational drug design from a fragment library are an efficient screen, a robust assay and atomic resolution structures of the protein-ligand complexes. However, not all targets are amenable to structure determination by x-ray crystallography or NMR. In particular, targets involved in diseases of protein misfolding are inherently intractable. In the absence of structures we are blind. However, we need not be deaf. The use of appropriate ligand detected NMR techniques can enable us to detect the effects of protein binding on the frequencies of the ligands. In our efforts to develop a treatment for α1 antitrypsin deficiency we have used saturation transfer difference (STD) NMR to detect hits from mixtures of compounds in a fragment library. In the absence of structures the initial challenge is threefold: 1. to distinguish between binding sites 2. to evaluate the relative affinities of hits and 3. to progress them to the stage where activity can be detected in biological assays. We largely achieved these aims by the use of CPMG NMR competition experiments that detect differential relaxation of the ligand upon protein binding. Further progression along the FBDD pathway relies upon the use of inter-ligand NOE experiments to develop fragment linking strategies.