My laboratory employs the-state-of-arts imaging methods such as high-resolution cryo-EM and single-molecule fluorescence energy transfer to study the structure and dynamics biological macromolecules as isolated molecules. The structural information often represents the real structure(s) of the molecule in action as opposed to that obtained by X-ray crystallography. To decipher the large amount of image data we obtain on daily basis, we are developing computation methods based on dimension reduction and machine learning, which have led to cryo-EM structures of RNA polymerase (2.5 Å), fish nodavirus (2.7 Å ), and methane monooxygenase (2.6 Å). We also use yeast genetics to develop novel chemical biology methods for labeling very large protein complexes. As a result, we have been able to watch the vibrations of the targeted subunit in real time. Now, we are dedicating those methods to drug development against the RNA-dependent RNA polymerase.