Recent advances in multidimensional NMR methodology have allowed the determination of protein structures larger that ~ 30 kDa. At the same time a number of new refinement strategies have been developed such as the use of a database potential or direct refinement against chemical shifts. The latest advance is the use of weak alignment of macromolecules in a magnetic field in dilute liquid crystalline media and measurements of residual dipolar couplings. These couplings provide unique long range information providing restraints for the determination of the relative orientation of structural elements as well as generally allowing substantial improvements in the quality of the overall structure.