How to construct protein chips and chemically labeling drug molecules without disrupting structures for HTS is still a challenging area. There are two main obstacles, one is that human multitrans membrane receptors, which are major drug targets, exhibit distinct motifs, and fold structures, and they will collapse unfold without membrane support in vitro; another one is that there still lack effective chemical labeling method for small drugs for detection. Therefore, how to acquire high detecting sensitivity for small molecules and to immobilize membrane protein receptors in native conformation with uniform direction on the chip, need to be solved for drug HTS. This paper reviews drug HTS trends in recent years, proposed a new virion-chip model and a feasible C-H activation method for CY-5 labeling drugs. It is expected to provide a good platform for future drug HTS.