Abstract Milk thistle ( Silybum marianum ) is a Mediterranean herb renowned for its liver-protective, antioxidant, anti-inflammatory, and detoxifying properties, primarily attributed to the bioactive compound silymarin. Recent studies have also highlighted its potential efficacy against COVID-19, contributing to the growing demand for milk thistle dietary supplements, particularly for liver health and immunity support. Milk thistle seeds, rich in silymarin and unsaturated fatty acids, hold significant industrial value as both medicinal and oilseed crops. To meet the growing demand, it is essential to develop standardized seeds, cultivation practices, and extraction methods aimed at maximizing yields of silymarin and other valuable metabolites. Recent advancements in genetic and genomic research, including the development of the first reference genome of S. marianum , have played a pivotal role in elucidating the biosynthesis pathways of silymarin and optimizing phytochemical production. This review highlights recent advancements in the genetics, genomics, and biochemistry of milk thistle, with particular emphasis on the importance of diverse genetic resources and AI-driven phenomics strategies, such as hyperspectral and RGB imaging, for high-yield and chemotype breeding. Further, feasibility of developing elite cultivars through molecular approaches, such as genome editing and metabolic engineering, is also discussed as the new traits obtained this way would be key to enhancing the commercial value of milk thistle in light of mass production of phytochemicals to meet rising market demands.