Abstract: Drug target discovery represents a central step in innovative drug discovery. However, conventional approaches for target identification face limitations in capturing transient, low-affinity, or low-abundance protein interactions. The emergence of chemical proteomics has provided breakthrough solutions to this bottleneck. This review highlights recent advances in photo-crosslinking technologies based on chemical proteomics for identifying targets of small molecule compounds. It focuses on how the integration of photoaffinity probes, bioorthogonal labeling, and high-resolution mass spectrometry enables global mapping of small molecule compound-target interaction networks within live cells. These technological breakthroughs pave new avenues for discovering novel therapeutic targets, elucidating drug mechanisms of action, and offering precise and effective therapeutic strategies for drug discovery.