Understanding the digestion of lipids and bioaccessibility of their derivate (lipid-soluble compounds/molecules) after digestion is very important to know as these compounds constitute a main part of the human's diet. In this chapter, two main aspects of digestion and bioaccessibility of the major lipid-soluble materials are discussed; a) the structure, metabolism, absorption, bioavailability, and bioaccessibility of lipid-soluble compounds/molecules (e.g. vitamins, polyphenols, sterols, etc.), b) the role of digestion in regard to the relationship between lipid digestion and bioaccessibility of fat-soluble compounds/molecules. It appears that the main aspects of the role of gastrointestinal digestion on bioavailability/bioaccessibility of lipophilic compounds are related to their molecular properties. While the role of the molecular form and linkage of the compounds during digestion is clear, the knowledge about gastrointestinal metabolites of most of the lipophilic compounds, their generation, and absorption is limited. Furthermore, it appears that the interactions between other nutrients and lipophilic compounds during gastrointestinal digestion, beside the organization of the mixed micelles in the real situation of multiple nutrients are yet to be fully described.