ABSTRACT Tachykinin peptides such as substance P (SP) function as neurotransmitters and neuromodulators in the mammalian central and peripheral nervous systems. Here, we provide evidence that they may also play an important role in the morphogenesis of some nonneural organs where epithelial-mesenchymal interactions are involved. We show the following. (1) mRNA encoding tachykinin precursor proteins is expressed transiently in condensing mes-enchyme during the development of mouse tooth germ, mammary gland, limb bud, external auditory meatus and genital tubercle. (2) In developing tooth germ and mammary gland; mRNA encoding the neutral endopepti-dase (NEP) that degrades secreted tachykinins is spatially and temporally co-expressed with tachykinin precursor mRNA. (3) SP and the mRNA encoding SP receptors are also expressed in the developing tooth germ. (4) Tooth development in explant cultures is blocked both by tachykinin-precursor-specific antisense oligonucleotide and by an SP receptor antagonist: in both cases the block is relieved by exogenous SP. Together, these findings suggest a surprising new role for tachykinins in tooth and mammary gland morphogenesis, and possibly also in limb, ear and external genitalia morphogenesis.