Antibiotic resistance poses an escalating global crisis as pathogens like the ESKAPE organisms –Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—are evolving to evade our antibacterial arsenal. We desperately need innovative strategies to fill the pipeline with effective treatments. BioSAXS, which maps antibiotic targets using X-ray scattering and biophysics, and artificial intelligence, which expedites drug creation and screening, are two promising approaches. In addition to conventional antibiotics, scientists are investigating immunotherapies, phage treatment, antimicrobial peptides, and synergistic combinations. Major challenges still exist, though, in turning these insights into licensed medical interventions. Enhanced public-private partnerships, improved data sharing, and incentives like milestone prizes could help spur the development of new antimicrobials. Regulators should consider pathways to accelerate approval for therapies that address urgent needs against resistant infections. The COVID-19 pandemic spotlighted concerning gaps in infectious disease preparedness that must be addressed. With global coordination and increased funding, we can reignite antimicrobial discovery and development to combat superbugs before routine injuries and illnesses become untreatable again. Overcoming the scientific and economic challenges will require commitment from all stakeholders. We urgently need imagination and resolve to build a robust pipeline of novel therapies to meet the threat of modern “superbugs” before the antibacterial era comes to an end.