Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure–activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic. Display omitted •This article provides over 500 natural and synthetic prenylated flavonoids from 2000 to 2021.•The diverse activities and structure–activity relationships of prenylated flavonoids are summarized.•The synthetic methodologies of prenylated flavonoids are summarized.