1 The guinea-pig hypogastric ganglion, perfused through its vasculature with physiological saline solutions, will respond repeatedly to nicotinic stimulant drugs injected at 4 min intervals into the perfusion stream. Stimulation is indicated by contraction of the vas deferens. After a varying number of doses of nicotinic stimulants, complete tachyphylaxis usually develops, and normally this persists for at least 1 hour. During this time, however, electrical stimulation of the hypogastric nerve is still fully effective.2 Tachyphylaxis may be reversed for varying periods of time by all of the following procedures: (a) tetanic stimulation of the hypogastric nerve; (b) injection of large doses of histamine, methacholine, or potassium chloride; (c) perfusion with saline containing ouabain 0.1 mug/ml or 80-100 mM lithium chloride, or, to a lesser extent, with potassium-free saline.3 Tachyphylaxis is always re-established with further doses of nicotinic stimulants, except during perfusion with lithium solutions.4 Atropine hastens the onset of tachyphylaxis, but does not prevent its reversal by hypogastric nerve stimulation or by histamine or potassium. However, it does prevent the reversal by methacholine and by lithium.5 Tachyphylaxis occurs in decentralized ganglia, and can be reversed by histamine, methacholine, and by tetanic stimulation of the hypogastric ganglion. Hence tachyphylaxis and its reversal cannot be due to an effect on presynaptic fibres.6 Potassium chloride stimulates the ganglion both before and after tachyphylaxis has developed to nicotinic drugs, and hence this is unlikely to be due to a depolarization block.7 It is concluded that tachyphylaxis could be due to a prolonged ganglionic hyperpolarization.