ConspectusBismuth, a heavy metal distinguished by its low toxicity, compared to lead or mercury, has long been associated with medicine for the treatment of various conditions, notably as a key component in triple and quadruple therapies for eradicating Helicobacter pylori, including antibiotic-resistant strains. Compounds such as bismuth subsalicylate (BSS) and colloidal bismuth subcitrate (CBS) enhance the efficacy of antibiotics, e.g., metronidazole and tetracycline. Over the past two decades, the knowledge on the molecular mechanism of action of bismuth drugs has been significantly advanced, in particular with the aid of the metallomics/metalloproteomics, facilitating the discovery of novel therapeutic applications beyond H. pylori eradication.This Account describes how the molecular mechanism of action of bismuth drugs was unveiled at a system level by multiple-metalloproteomics approaches, which enable the comprehensive identification of bismuth-binding proteins with diverse affinities in bacteria. By integration with other techniques such as proteomics, bioinformatics and molecular biology, the sustained efficacy of bismuth drugs was attributable to their capacities to disrupt multiple biological pathways through binding and functional perturbation of key enzymes, in particular, those enzymes bearing CXnC (n = 2, 7), CXnH (n = 5, 6) and HXnH (n = 0-2, 8) motifs, in consistence with the thiophilic nature and high acidic property of bismuth.The generated knowledge on the mode of action of bismuth drugs lays a solid foundation for further exploration of their novel therapeutic applications. Our extensive studies have revealed that bismuth drugs and compounds hold great potential as versatile agents in combating antimicrobial resistance (AMR) crisis through co-therapies with clinically used antibiotics. This includes bismuth drugs as broad-spectrum inhibitors of metallo-β-lactamases (MBLs), enzymes responsible for resistance to β-lactam antibiotics, to fight against MBLs-positive bacterial infection together with β-lactams; bismuth drugs serve as adjuvants of Cefiderocol (Fetroja), the only clinically approved sideromycin, against infections caused by multidrug-resistant Pseudomonas aeruginosa and Burkholderia cepacia; bismuth drugs (and relevant compounds) in combination with clinically used antibiotics could combat Pseudomonas aeruginosa infections by disrupting iron homeostasis and functionally impairing Fe-S cluster-containing enzymes in multidrug-resistant Pseudomonas aeruginosa; newly developed bismuth compounds serve as novel metalloantibiotics to combat AMR. Moreover, the ability of bismuth to disrupt key zinc finger proteins for the transcription and replication in coronavirus rendered its new potential in treating coronavirus infections, particularly SARS-CoV-1 and SARS-CoV-2. Combining clinically used bismuth drugs with N-acetyl cysteine (NAC), a thiol-containing drug, increases bismuth uptake in blood plasma to therapeutic levels for SARS-CoV-2 without apparent toxicity. Bismuth drugs, therefore, hold great potential for the treatment of viral infections.We anticipate that our mechanism-guided discoveries of bismuth's new therapeutic applications are poised to inspire researchers in relevant fields to rationally design drugs (and metallodrugs) and repurpose FDA-approved drugs, ultimately leading to the development of new effective therapeutics for combating emerging infectious diseases, which will positively impact human health and well-being.