Protein conformational changes are often associated with their biol. functions. On the other hand, many disease relevant mutations may cause conformational changes or tip the balance of conformational dynamics. Therefore, small mols. that can restore the "normal" conformation or conformational dynamics could be potential therapeutics to treat diseases. However, such small mols. may not be found via traditional screening methods. SHG is a powerful screening technol. that can detect subtle conformational change of a membrane bound protein or protein complex upon ligand binding. This screening method is sensitive and high throughput. This talk will provide a few examples of applying SHG to protein targets from different classes to identify novel MoA, binding site or chemotype.