Natural products remain an invaluable resource in the ongoing search for new medicines, offering a vast array of bioactive compounds with diverse pharmaceutical applications. Plants, animals, and microbes contribute extensively as sources of specialized metabolites with medicinal properties characterized by their extensive chemical diversity. These natural compounds serve as drug prototypes, leads, or pharmacological tools interacting with various biological targets. Notable natural product drug discoveries include the cardiotonic digoxin from Digitalis species, the antimalarial artemisinin from Artemisia annua, the anticancer taxol from Taxus species, and podophyllotoxin from Podophyllum peltatum, the latter spurring synthesis of the anticancer medication etoposide. However, biodiversity loss poses a mounting threat that could severely impact drug discovery from nature. This special issue will address the global threat to biodiversity and emphasize on the wealth of undiscovered natural products across terrestrial and marine habitats that hold promise as the next generation of drug leads. It will provide cutting-edge perspectives on identification strategies, bioactivity evaluations, organic syntheses, biological assays, and other approaches critical to elucidating mechanisms and assessing suitability of promising natural products at various stages of drug development. Ranging from early discovery phases to preclinical and clinical evaluations, this issue highlights the myriad facets of contemporary research at the intersection of natural products and drug discovery.