Phenolic compounds are a class of secondary metabolites widely distributed in plant tissues to serve as a pivotal defense mechanism against ecological and physiological threats like ultraviolet radiation, bacterial growth, and herbivore predation. Grapes (Vitis vinifera) are commonly used as the primary raw materials in winemaking, leaving grape skin and seeds as residues, collectively referred to as wine pomace. Epidemiological studies have shown that grape skin’s potent health-promoting effects, including antioxidant, antiproliferative, anti-inflammatory, and antibacterial activities, are primarily due to the high contents of phenolic compounds such as tannins, anthocyanins, and flavonols, which are predominantly found in the hypodermal layers of the skin. These phenolic compounds from grape skin offer multifaceted protective benefits, justifying their potential applications in developing functional foods, dietary supplements, and pharmaceuticals while promoting environmental sustainability. The extraction of phenolic compounds from the grape skin matrix is the first step in valorizing this winery by-product, and a thorough understanding of the extraction methodologies is crucial for maximizing the yield while preserving the bioactivity of the phenolic compounds. This chapter describes the methodologies used to separate, identify, and fractionate phenolic compounds from grape skin.