In drug discovery, solution NMR is usually considered a method of choice for highly soluble small to moderate sized proteins where the limitations of rapid T2 relaxation are not prohibitive. But many drug targets are large proteins that produce broad NMR signals, whilst other targets are poorly soluble at concentrations required for multidimensional NMR. Should NMR then be avoided? Not necessarily. The use of appropriate ligand-detected NMR techniques can enable us to detect the effects of protein binding on the resonances of ligands. The differential relaxation properties of small and large molecules can be exploited using CPMG pulse sequences to detect ligand binding even at low protein concentrations. Moreover, the efficiency of transfer of NOE magnetization in large complexes and the retention of NOE derived magnetization in dissociated ligands enables information to be gleaned from transient binding events. Here we present the use of such techniques in two case studies of large proteins. The first is in fragment-based drug discovery screening and hit optimization for the 52 kDa serpin, Z-antitrypsin; a poorly soluble target involved in a disease of protein misfolding. The second target is the trimeric 180 kDa poxvirus protein D13, where ligand detected techniques are used to probe protein-protein interactions involved in virion formation and to explore their potential disruption by small molecules.