The effects of substance P and other peptides were studied on the neurons of isolated spinal cord of the frog. Substance P and certain related peptides, which have a common C-terminal sequence, -Phe-X-Gly-Leu-Met-NH2 (where X=Ile, Tyr or Phe), exerted a remarkably strong excitant action on spinal motoneurons. On a molar basis, substance P was about 200 times, physalaemin 1500 times, and eledoisin 2000 times more active thanl-glutamate in depolarizing the spinal motoneuron in 0.4 mM Ca-Ringer's solution. Since the depolarizing action of substance P and related peptides persisted after the synaptic transmission was blocked by Ca-deficient (0–0.2 mM) Ringer's solution or by tetrodotoxin (10−8−10−7 g/ml), it was concluded that these peptides have a direct action on the motoneurons to induce the depolarization.