Bitter taste receptors (TAS2Rs), initially identified for their role in detecting bitter compounds in the oral cavity, have emerged as multifunctional receptors with critical roles beyond taste perception. These G protein-coupled receptors are expressed in various extra-oral tissues, where they influence immune responses, inflammation, and cellular processes associated with both infectious and chronic diseases. TAS2Rs play a key role in pathogen detection, immune modulation, and physiological regulation, contributing to defense mechanisms and homeostasis across multiple systems, including the respiratory, cardiovascular, metabolic, and central nervous systems. Their unique signaling pathways, broad ligand specificity, and genetic polymorphisms highlight their complex roles in health and disease. As our understanding of TAS2Rs deepens, these receptors are gaining recognition as potential therapeutic targets for managing a wide range of conditions. However, significant challenges remain, including interspecies variability and the limited in vivo characterization of their functions. Advances in technologies such as cryo-electron microscopy and transgenic models are providing valuable insights into TAS2R structure and function, paving the way for the development of novel therapeutic strategies. This review explores the expanding landscape of TAS2R research, emphasizing their emerging importance in addressing pressing global health challenges.