Abstract: Heteromeric amino acid transporters (HATs), assembled from members of the SLC3 and SLC7 families, are key transporters that mediate the transmembrane transport of amino acids, neurotransmitters, and a variety of drug molecules. The functional homeostasis of HATs is essential for maintaining cellular nutrient sensing, redox balance, and neurotransmission. Dysregulation of HATs has been closely associated with tumor metabolic reprogramming, resistance to ferroptosis, and inherited aminoacidurias, and they have therefore long been regarded as important targets for drug development. In this review, we systematically summarize recent advances in the structural biology of the HAT family, with particular emphasis on the molecular basis underlying substrate selectivity and ion coupling among different members. Building on these insights, we further highlight the latest progress in structure-based drug design (SBDD). By integrating multiple inhibitor-bound complex structures, we analyze two emerging inhibitory strategies: enhancing ligand affinity through exploitation of non-conserved hydrophobic side pockets, and blocking the transport cycle by disrupting the secondary structures of transmembrane helices TM3 and TM10. Collectively, these insights provide an important structural framework and new perspectives for the development of highly selective HAT inhibitors and related therapeutic strategies.