For sweet, salty, sour, and umami flavors, the tongue has only one type of receptor. For bitter compounds, the human tongue possesses at least 25 different chemoreceptors—and most of these bitter receptor types have multiple genetic variants, resulting in considerable individuality in responsivity to bitter substances. Though our understanding of bitter receptor function is limited, bitter receptors may have evolved as a means of discouraging the ingestion of toxins. However, their presence in many non-oral tissues and functional variability suggests that their significance to health goes far beyond taste perception. Bitter ‘taste’ receptors have been found in immune cells, the brain, airways, skin, liver, kidneys, testes, ovaries, nasal sinuses, heart, thyroid gland, bones, breasts, pancreatic beta cells, and intestines. For this reason, bitter receptors may be useful molecular targets in immune, metabolic, and endocrine conditions. In this review, the authors detail mechanisms through which bitter receptor ligands may impact innate immunity, digestive secretion, thyroid hormone production, smooth muscle contraction, the glycemic response, and other diverse functions. They also describe genetic polymorphisms in bitter receptors and their health effects in humans and animals.