Although Cannabis sativa synthesizes a wide range of phytochemicals, much attention has been primarily given to two phytocannabinoids, ?9-tetrahydocannabinol (THC) and cannabidiol (CBD), due to their distinctive activities in humans. These bioactivities can be further enhanced through the interaction of THC and CBD with other phytocannabinoids or non-phytocannabinoid chemicals, such as terpenes and flavonoids, a phenomenon that is termed the entourage effect. Flavonoid metabolism in C. sativa and the entourage effect are currently understudied. This mini-review examines recent advances in the biosynthesis and bioactivities of cannflavins, which are prenylated (C5) and geranylated (C10) flavones that are relatively unique to C. sativa. We also discuss the rapidly developing omics tools that enable discoveries in flavonoid metabolism in C. sativa and manipulation of flavonoid production through biotechnology. These advances set the stage for interrogating the health benefits of C. sativa flavonoids, deciphering the contribution of flavonoids to the entourage effect, and developing drugs.