One of the most desired features of low‐molecular‐weight therapeutic molecules (“small molecules”) is their specificity towards drug‐related target(s) in order to minimize adverse effects in humans. Improving specificity involves a high degree of optimization of structural information. X‐ray crystallography and NMR spectroscopy are the two major techniques for obtaining precise protein–ligand complex structures. The structure determination of protein–ligand complexes can be based on a variety of NMR data. Resonance assignment of the NMR signals from NMR‐active nuclei in the protein and the ligand with subsequent nuclear Overhauser effect spectroscopy (NOESY) analysis revealing cross‐peaks within and between ligand and protein is the classical method. It results in the most valuable information, because nuclear Overhauser effect (NOE) signals can directly be converted into distance restraints. This approach can, however, be very time‐consuming and, more importantly, often fails in cases of low or intermediate affinity, where NOEs cannot be observed at the interface of protein and ligand due to intermediate chemical exchange phenomena. In the last decade, methods have been developed to shortcut the classical procedure. Fast methods for strong binders are still NOE‐based, but do not require chemical shift assignment of the protein. Initial binders identified in fragment screens from an NMR‐driven drug discovery process are often weak and do not show intermolecular NOEs. Therefore, additional experimental restraints other than NOEs can be collected and transferred to restraints in the calculations to solve the structural problem. In this chapter, we report on the computational use of different NMR experiments including unassigned NOEs, saturation transfer difference, WaterLOGSY, paramagnetic shifts, and, in the most detail, ligand‐induced chemical shift perturbations.