Display omitted •Orsellinic acid derived meroterpenoids contain several promising drug candidates.•Recent studies have elucidated the molecular bases for their biosynthetic machineries.•Enzymology of biosynthetic enzymes provides strategies for engineered biosynthesis.•Engineered biosynthesis contributes to generate a supply of novel molecules for drug discovery. The advent of synthetic biology has yielded fruitful studies on orsellinic acid-derived meroterpenoids, which reportedly possess important biological activities. Genomics and transcriptomics have significantly accelerated the discovery of the biosynthetic genes for orsellinic acid-derived fungal and plant meroterpenoids. Subsequently, a well-developed heterologous host provides a convenient platform to generate a supply of useful natural products. Furthermore, in vitro reconstitution and genome editing tools have been increasingly employed as efficient means to fully understand the enzyme reaction mechanisms. With the knowledge of the biosynthetic machinery, combinatorial and engineered biosyntheses have yielded novel molecules with improved bioactivities. These studies will lay the foundation for the production of meroterpenoids with novel medicinal properties.