This review updates the current clinical trials data on the health benefits of polymethoxyflavones (PMFs), a group of flavanones found in citrus fruits. PMFs have been shown to possess various biological activities, including anticancer, anti-inflammatory, anti-atherosclerosis, and neuroprotective effects. However, the understanding of their metabolism in humans and their direct effects on human health remains limited. The review highlights the lack of information on the bioavailability and metabolism of PMFs, including their pharmacokinetics, human phase I and II metabolites in biological fluids and tissues, and gut microbiota metabolism. The chemical structure of PMFs, their occurrence in citrus fruits, and their extraction methods are also discussed. In vitro and in vivo studies demonstrate the health-promoting effects of PMFs, such as regulation of differentiation, proliferation, angiogenesis, and metabolism through modulation of signaling cascades, gene transcription, and protein function. Despite promising results, there are limitations in the dosage and administration approaches of PMFs, and more detailed clinical studies are needed to understand their pharmacokinetics and main metabolites in circulation, tissues, or biological fluids.This review updates the current clinical trials data on the health benefits of polymethoxyflavones (PMFs), a group of flavanones found in citrus fruits. PMFs have been shown to possess various biological activities, including anticancer, anti-inflammatory, anti-atherosclerosis, and neuroprotective effects. However, the understanding of their metabolism in humans and their direct effects on human health remains limited. The review highlights the lack of information on the bioavailability and metabolism of PMFs, including their pharmacokinetics, human phase I and II metabolites in biological fluids and tissues, and gut microbiota metabolism. The chemical structure of PMFs, their occurrence in citrus fruits, and their extraction methods are also discussed. In vitro and in vivo studies demonstrate the health-promoting effects of PMFs, such as regulation of differentiation, proliferation, angiogenesis, and metabolism through modulation of signaling cascades, gene transcription, and protein function. Despite promising results, there are limitations in the dosage and administration approaches of PMFs, and more detailed clinical studies are needed to understand their pharmacokinetics and main metabolites in circulation, tissues, or biological fluids.