Abstract: The complex network formed by protein-protein interaction (PPI) underpins a series of core life processes such as signal transduction, cell proliferation, and DNA repair. Correspondingly, the disorders of these interactions often become the driving factors of various human diseases. Therefore, targeting PPI has become a highly promising research direction in the field of new drug development. This review mainly summarizes the mechanism, clinical efficacy and safety of marketed drugs and drugs under clinical research, the analysis of PPI interfaces of the targets acted upon by marketed drugs, the features and druggability challenges of PPI associated with transcription factor, dynamic protein and multi-component complex, the applicability of screening strategies such as fragment-based drug design for discovering PPI modulators, along with emerging technologies in target identification, molecular discovery and regulatory-mode characterization. It highlights that modulation of dynamic conformational ensembles represents the future developmental trend of this field, and offers theoretical reference and strategic insights for the subsequent development of novel PPI-modulating therapeutics.