Profiling human interactome is critical in understanding the molecular basis for nearly all processes of life. Over the years, we’ve advanced crosslinking mass spectrometry by developing experimental methods and software tools to identify tens of thousands of PPIs from whole cells. These data reveal numerous aspects of living systems - for example protein subcellular localizations, virus-host interactions, and architectures of suprabiomolecular machineries. Furthermore, these data offer unprecedented opportunities to profile interactome changes between tissues and disease states, providing invaluable training data for AI-based methods to identify PPI-mediating motifs, inform new protein/antibody designs and screen for drug targets.