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Background: The inherent poor druggability of numerous active pharmaceutical ingredients (APIs) necessitate the modification of their physicochemical and biopharmaceutical properties to enhance their bioavailability and therapeutic effectiveness. Fatty acid conjugation, termed fattigation technology by our research group, represents a versatile pharmaceutical platform in drug delivery by chemically binding of carboxyl group of fatty acids and hydroxy or amine group of target molecules, resulting in modifying the physicochemical and biopharmaceutical properties of APIs or target molecules and creating diverse self-assembled amphiphilic structures. These fattigated structures offer several advantageous features, including 1) improved solubility of many poorly water-soluble drugs via nanonization process, 2) enhanced the membrane permeability, 3) induced enzyme-oriented degradation for controlled release of peptides/drugs, 3) enabled long-acting drug performance, and 4) enhanced anti-tumor activity by receptor-mediated drug delivery. Area covered: This review covers recent advances and relevant researches on fattigation technology, encompassing various aspects of fatty acid conjugation, including design principles involving different types of fatty acids and conjugation strategies, and their applications in the pharmaceutical fields. Expert opinion: We address the pharmaceutical challenges associated with fattigation technology. Particularly, we focus on the choice and substitution content of fatty acids in conjugates for self-assembly and nanonization to achieve desirable physicochemical and biopharmaceutical characteristics, such as solubility, permeability, release rate, controlled-cytotoxicity, bioavailability, targetability and therapeutic effectiveness. Additionally, we offer insights into the future prospects of this fattigation technology by introducing the application of noninvasive delivery of fattigated peptide/protein drugs and the potential delivery of fatty acids for synergistic biological activities to boost therapeutic outcomes.