Natural products (NPs) have historically played a key role in drug discovery, particularly for cancer and infectious diseases, but also in other therapeutic areas. NPs offer unique structural diversity and complexity, with higher molecular mass, more sp³ carbon atoms, and oxygen atoms, but fewer nitrogen and halogen atoms, and higher numbers of hydrogen bond donors and acceptors. These properties make NPs valuable for drug discovery, especially for targeting protein-protein interactions. However, challenges in NP-based drug discovery include the difficulty of screening, isolation, and characterization of NPs, as well as issues with intellectual property and regulatory compliance. Recent technological advances, including improved analytical tools, genome mining, and microbial culturing, are addressing these challenges and revitalizing interest in NPs as drug leads, particularly for combating antimicrobial resistance. Analytical techniques such as metabolomics and high-resolution mass spectrometry are enabling the identification and characterization of NPs, improving dereplication and accelerating the discovery of novel compounds. Genome mining and engineering are also key areas of progress, allowing the identification and manipulation of biosynthetic gene clusters to produce new NPs. Cultivation systems are being developed to overcome the challenges of culturing uncultivated microorganisms, with approaches such as co-culturing and in situ incubation enabling the discovery of new NPs. These advances are helping to overcome the limitations of traditional NP-based drug discovery, opening up new opportunities for the development of novel therapeutics.Natural products (NPs) have historically played a key role in drug discovery, particularly for cancer and infectious diseases, but also in other therapeutic areas. NPs offer unique structural diversity and complexity, with higher molecular mass, more sp³ carbon atoms, and oxygen atoms, but fewer nitrogen and halogen atoms, and higher numbers of hydrogen bond donors and acceptors. These properties make NPs valuable for drug discovery, especially for targeting protein-protein interactions. However, challenges in NP-based drug discovery include the difficulty of screening, isolation, and characterization of NPs, as well as issues with intellectual property and regulatory compliance. Recent technological advances, including improved analytical tools, genome mining, and microbial culturing, are addressing these challenges and revitalizing interest in NPs as drug leads, particularly for combating antimicrobial resistance. Analytical techniques such as metabolomics and high-resolution mass spectrometry are enabling the identification and characterization of NPs, improving dereplication and accelerating the discovery of novel compounds. Genome mining and engineering are also key areas of progress, allowing the identification and manipulation of biosynthetic gene clusters to produce new NPs. Cultivation systems are being developed to overcome the challenges of culturing uncultivated microorganisms, with approaches such as co-culturing and in situ incubation enabling the discovery of new NPs. These advances are helping to overcome the limitations of traditional NP-based drug discovery, opening up new opportunities for the development of novel therapeutics.