Flavonoids comprise a structurally diverse family of plant-derived polyphenols recognized for their antioxidant, anti-inflammatory, immunomodulatory, and cell-signaling activities demonstrated across a broad range of preclinical models. Clinical translation, however, has been inconsistent. Numerous randomized controlled trials and smaller human studies have assessed both dietary flavonoid-rich preparations and purified compounds, including quercetin, cocoa flavanols, and isoflavones (and their metabolites, such as equol), as well as flavonoid-based adjunctive therapies in cardiovascular, metabolic, neurocognitive, inflammatory, dermatological, and oncological contexts. Despite these encouraging findings, interpretation is constrained by substantial heterogeneity in study design, product standardization, dosing strategies, bioavailability, and outcome selection. Many contemporary trials continue to depend on surrogate biomarkers rather than rigorously validated clinical endpoints, a practice that can limit the interpretability of therapeutic outcomes. Although research in this area has progressed, many studies still overlook the fact that individuals metabolize and eliminate compounds differently, which often explains why results vary significantly or cannot be reproduced reliably. Recently, scientists have begun to turn toward more practical and innovative approaches, for example, using advanced drug-delivery formulations, studying how the gut microbiome influences metabolic activity, and identifying omics-based biomarkers. This chapter takes a closer look at the present state of clinical studies on flavonoids. It not only reviews the major trials that have been completed so far but also discusses those that are currently underway. In doing so, it highlights the persistent challenges that limit progress, including issues related to pharmacokinetics, study design, and regulatory barriers. The chapter also puts forward practical suggestions to improve future research, determining appropriate dosage levels, selecting mechanistic endpoints that truly reflect clinical outcomes, and applying more rigorous and transparent trial methodologies. Collectively, these recommendations are intended to strengthen the scientific basis for flavonoid-based therapies and encourage their wider adoption in both medical treatment and preventive healthcare.