A quantitative structure-activity relationship (QSAR) study has been performed on the toxicity of organic compounds to the tadpole, Rana temporaria. The biological test data were taken from Charles Ernest Overton's classic monograph Studien über die Narkose, which has been widely cited by researchers studying the correlation of biological activity with partition coefficient and the mechanism of anesthesia. A baseline narcosis QSAR model, log (1/C = 0.909 log P + 0.727, was derived using data on 18 alcohols, ketones, and hydrocarbons, where C is the lowest narcosis-inducing concentration in moles per litre, and P is the n-octanol/water partition coefficient. The corresponding lowest tadpole test concentration producing narcosis or other toxic effects for the remaining 100 compounds was compared with that predicted by the above QSAR equation. In general, very good agreement was obtained between the predicted and measured values for those nonelectrolytes producing solely a narcosis physiological response. In contrast, acetamide, succinimide, urea, and ethylene glycol produced lethality without narcosis at considerably lower concentrations than predicted. These compounds, which have low lipoid solubility and undergo little or no membrane transport, produce osmotic effects. The observed and predicted narcotic concentrations for the two hypnotic agents, sulfonal and trional, are in general agreement, based upon log P values calculated from the water solubility and melting point. The lack of observed effect for cetyl alcohol, anthracene, anthraquinone, parachloralose, and terpin hydrate, even in tadpole tests of long duration, can be attributed to a water solubility limitation, or cutoff, that is due to a high log P, a high melting point, or a combination of these factors. Although coumarin is 17 times more toxic than predicted, it produces reversible narcosis effects only. This behavior may reflect a reversible Michael-type addition by nucleophilic moieties present in mole cules comprising the membrane lipoid site of action. Alkaloids and strongly basic amines are all more toxic than predicted.