Since the inventions of hybridoma in 1970s and phage panning in 1990s, numerous technologies have been developed for the discovery and engineering of mAbs, the powerhouse of biopharmaceutical industry to date. However, it is still a daunting challenge for developing therapeutic mAbs against difficult targets. Examples of so called high-hanging fruits include (1) antibodies not only binding but also rendering functions needed for therapy, such as enzyme inhibition and broad neutralization against viruses; (2) mAb modulators of membrane proteins including GPCRs and ion channels; and (3) biologics able to penetrate the blood-brain barrier (BBB).