(1) The capsaicin used in the physiological and pharmacological observations (in animals and human beings) chemically represents different chemical compounds, which can be obtained from the plants (paprika, chilli, etc.), (2) capsaicinoids are able to modify the capsaicin-sensitive afferent nerves, which have principle roles in the defence of different organs (including the gastrointestinal tract [against the different chemicals, heat, strech, chemical millieu-induced damage], (3) the application of capsaicin (capsaicinoids) can be repeated for the beneficial effects on the gastrointestinal tract as those in animal experiments. After this interdisciplinary and critical review, this paper demonstrates the well-planned research pathways of the discoveries of capsaicinoids from plant chemistry, via physiology, pharmacology and toxicology in animal experiments and human observations.