Conditions which affect the response of smooth muscle to repeated application of stimulating drugs have been investigated. In guinea-pig taenia coli, tension changes were recorded simultaneously with membrane potential changes using the sucrose gap technique. Acetylcholine, histamine, and 5-hydroxytryptamine caused depolarization and, after removal of the drug, hyperpolarization which was followed by a sequence of damped oscillations of the membrane potential. The average rate of depolarization decreased in the order acetylcholine>histamine >5-hydroxytryptamine. The readiness with which tachyphylaxis occurred increased in the order acetylcholine<histamine<5-hydroxytryptamine. When a dose of a stimulating drug was repeated, the response obtained depended on the phase of the oscillatory potential changes during which it was applied. In general the effect was depressed during a phase of polarization and enhanced during a phase of depolarization. The degree of tachyphylaxis-or potentiation-depended not only on the direction in which the membrane potential changed at the moment of drug application, but also on the relation between the rate at which this potential change took place and the rate of depolarization caused by the drug. The results observed are consistent with the hypothesis that the fluctuating excitability and polarization of the smooth muscle membrane is brought about by periodical changes in the rate of active ion transport and other stabilizing processes in the cell membrane which depend on the rate of metabolic energy supply. The muscle was sensitized to acetylcholine and histamine by previous treatment with, or in the presence of, 5-hydroxytryptamine.