The partially purified substance P markedly reduced blood pressure and contracted gastrointestinal (GI) smooth muscle. It was found to be a peptide of 11 amino acids. SP bears a C-terminal sequence and spectrum of biological activities similar to those of other peptides collectively named “tachykinins”. These peptides have largely been isolated from the amphibian skin with the exception of eledoisin that is present in octopus salivary glands. In the course of purifying SP, another substance was discovered that produced cutaneous vasodilation and cyanosis and was chemically distinguishable from SP. This preparation was named neurotensin (NT) and was subsequently determined to be a tridecapeptid. Structures of SP, neurotensin (NT), and natural homologs are explained in this chapter. The anatomical and physiological characteristics of these peptides in the GI tract and structural requirements for their biological activity in this and other peripheral systems are discussed in the chapter. Substance P's distribution in the gut, biological activity, and structure–activity relationships are also discussed in this chapter. The relative biological activities of SP and its fragments are tabulated. Natural analogs of SP are discussed in the chapter. For neurotensin, distribution in the gut, biological activity, and structure–activity relationships are described in the chapter. The relative biological activities of NT and its fragments are tabulated. Natural analogs of SP are discussed in the chapter. SP and NT, peptides with a dual localization in the mammalian brain and gut, have many potent actions upon GI and other peripheral organ systems. Recent investigations have disclosed determinants within their structures responsible for the biological activity; the C-terminal amino acids of both peptides are important in this respect. The design and synthesis of the novel peptide analogs may yield biologically-stable compounds of high potency for the treatment of disorders of intestinal motility or ion transport, cardiovascular disease, or endocrine abnormalities.