Antibiotic-resistant pathogens are increasingly prevalent, necessitating the development of new antibiotics. However, progress in this area has been slow due to the limited number of molecular scaffolds used in antibiotics and the rise of multidrug resistance. New scaffolds are needed to combat these resistant strains. Promising approaches include exploring underexplored microbial niches for natural products, designing screens to avoid rediscovering old scaffolds, and repurposing synthetic molecules as antibiotics. The global antibiotics market is dominated by classes discovered over half a century ago, with most new antibiotics being derivatives of these scaffolds. This has led to a decline in antibiotic discovery and development, exacerbated by the economics of antibiotic development, which yield lower revenues compared to other drugs. The challenge is to find new classes of antibiotics to address the growing threat of resistance. Emerging antibiotic-resistant pathogens include MRSA, multidrug-resistant Gram-negative bacteria, and MDR-TB and XDR-TB. These pathogens pose significant threats to public health. The history of antibiotic development shows that only four new classes have been introduced since the 1960s, with most new antibiotics being chemical derivatives of existing scaffolds. Natural products and their semisynthetic derivatives account for most clinically-used antibiotics. However, natural product discovery has declined due to scaffold rediscovery and the difficulty in finding new antibiotics. Recent efforts to search underexplored ecological niches and bacterial taxa have yielded novel molecules, while new screening strategies have begun to circumvent the problem of rediscovery. Fully synthetic molecules are crucial in the current antibiotic arsenal, but recent efforts to discover new synthetic scaffolds have not been successful. The success of repurposing external compound libraries, as demonstrated by Pfizer, highlights the potential of this approach. Target-based discovery has faced challenges, but retooled strategies can play an important role in finding new antibiotics. New scaffolds for old targets and grouping new targets by inhibitor class are promising strategies. For example, targeting Lipid II and developing new scaffolds for existing targets can avoid cross-resistance. The development of new scaffolds for ATP-binding enzymes and other targets is also promising. The need for new antibiotics remains urgent, and the discovery of new scaffolds is essential for combating resistance. The future of antibiotic development depends on innovative approaches to scaffold discovery and the exploration of underexplored microbial niches.Antibiotic-resistant pathogens are increasingly prevalent, necessitating the development of new antibiotics. However, progress in this area has been slow due to the limited number of molecular scaffolds used in antibiotics and the rise of multidrug resistance. New scaffolds are needed to combat these resistant strains. Promising approaches include exploring underexplored microbial niches for natural products, designing screens to avoid rediscovering old scaffolds, and repurposing synthetic molecules as antibiotics. The global antibiotics market is dominated by classes discovered over half a century ago, with most new antibiotics being derivatives of these scaffolds. This has led to a decline in antibiotic discovery and development, exacerbated by the economics of antibiotic development, which yield lower revenues compared to other drugs. The challenge is to find new classes of antibiotics to address the growing threat of resistance. Emerging antibiotic-resistant pathogens include MRSA, multidrug-resistant Gram-negative bacteria, and MDR-TB and XDR-TB. These pathogens pose significant threats to public health. The history of antibiotic development shows that only four new classes have been introduced since the 1960s, with most new antibiotics being chemical derivatives of existing scaffolds. Natural products and their semisynthetic derivatives account for most clinically-used antibiotics. However, natural product discovery has declined due to scaffold rediscovery and the difficulty in finding new antibiotics. Recent efforts to search underexplored ecological niches and bacterial taxa have yielded novel molecules, while new screening strategies have begun to circumvent the problem of rediscovery. Fully synthetic molecules are crucial in the current antibiotic arsenal, but recent efforts to discover new synthetic scaffolds have not been successful. The success of repurposing external compound libraries, as demonstrated by Pfizer, highlights the potential of this approach. Target-based discovery has faced challenges, but retooled strategies can play an important role in finding new antibiotics. New scaffolds for old targets and grouping new targets by inhibitor class are promising strategies. For example, targeting Lipid II and developing new scaffolds for existing targets can avoid cross-resistance. The development of new scaffolds for ATP-binding enzymes and other targets is also promising. The need for new antibiotics remains urgent, and the discovery of new scaffolds is essential for combating resistance. The future of antibiotic development depends on innovative approaches to scaffold discovery and the exploration of underexplored microbial niches.