Natural products (NPs) have historically played a significant role in drug discovery, particularly for cancer and infectious diseases. However, technical challenges in screening, isolation, characterization, and optimization have led to a decline in their use by the pharmaceutical industry since the 1990s. Recent technological advancements, including improved analytical tools, genome mining, and engineering strategies, are addressing these challenges and revitalizing interest in NPs as drug leads, especially for tackling antimicrobial resistance. NPs offer unique advantages over synthetic molecules, such as higher molecular mass, more complex 3D structures, and greater hydrophilicity. However, they also present challenges, including the complexity of their structures and the difficulty in identifying and characterizing bioactive compounds. Advances in analytical techniques, such as high-resolution mass spectrometry and metabolomics, are enabling more efficient and accurate identification of NPs. Genome mining and engineering strategies, including the use of CRISPR-Cas9 technology, are facilitating the discovery of new NPs by identifying and expressing biosynthetic gene clusters in heterologous hosts. Microbial culturing systems have also evolved to better mimic natural environments, increasing the likelihood of identifying novel NPs. Strategies such as co-culturing and in situ incubation are being used to promote NP production and access previously uncultured microorganisms. These advancements are opening up new opportunities for NP-based drug discovery, particularly in addressing antimicrobial resistance and other therapeutic areas.Natural products (NPs) have historically played a significant role in drug discovery, particularly for cancer and infectious diseases. However, technical challenges in screening, isolation, characterization, and optimization have led to a decline in their use by the pharmaceutical industry since the 1990s. Recent technological advancements, including improved analytical tools, genome mining, and engineering strategies, are addressing these challenges and revitalizing interest in NPs as drug leads, especially for tackling antimicrobial resistance. NPs offer unique advantages over synthetic molecules, such as higher molecular mass, more complex 3D structures, and greater hydrophilicity. However, they also present challenges, including the complexity of their structures and the difficulty in identifying and characterizing bioactive compounds. Advances in analytical techniques, such as high-resolution mass spectrometry and metabolomics, are enabling more efficient and accurate identification of NPs. Genome mining and engineering strategies, including the use of CRISPR-Cas9 technology, are facilitating the discovery of new NPs by identifying and expressing biosynthetic gene clusters in heterologous hosts. Microbial culturing systems have also evolved to better mimic natural environments, increasing the likelihood of identifying novel NPs. Strategies such as co-culturing and in situ incubation are being used to promote NP production and access previously uncultured microorganisms. These advancements are opening up new opportunities for NP-based drug discovery, particularly in addressing antimicrobial resistance and other therapeutic areas.