Bitter taste-sensing type 2 receptors (TAS2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), play a key role in the perception of bitterness. Although initially, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, recent studies have demonstrated the presence of these sensory receptor genes and proteins in several extra-oral tissues, such as, e.g., gastric, intestinal, lung, pancreatic, adipose or ovarian tissues. Following their ubiquitous presence, critical points of extra-oral TAS2Rs biology, such as their structure, cellular and metabolic functional roles, signaling transduction pathways, mutational polymorphism, and molecular evolution, have been and still are widely studied. The TAS2R signaling cascade, for instance, has been demonstrated to be a pivotal modulator of inflammatory processes and innate immunity in a number of organs and tissues of the gastro-intestinal tract, the lung and immune-competent cells of the blood. The latest advances in this field raise the possibility of utilizing TAS2Rs as therapeutic targets for inflammation-associated diseases. The focus of this review is (1) to provide an update on the latest findings from in vitro and in vivo studies regarding the expression and the molecular basis of TAS2Rs' functional role in inflammatory processes in extra-oral tissues, and (2) to — considering clinical findings — discuss the therapeutic potential of TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, and/or pharmacological profiles.