Acute tolerance can be defined as a decrease in response to alcohol within a single exposure to the drug, which occurs independently of changes in blood alcohol concentrations (BACs). BACs change over time in most human alcohol administration studies, and computational techniques that account for these changes must be used to measure the rate of acute tolerance development. The most widely used acute tolerance measure in human research is often called the Mellanby effect, and involves the comparison of responses at the same BAC on the ascending and descending limbs of the blood alcohol curve. We compared the Mellanby measure with two other measures of acute tolerance: a conceptually similar area under the curve measure, and a slope function approach that used data only from the descending limb of the blood alcohol curve. The measures were intercorrelated and discussed with regard to empirical and conceptual issues. Exploratory comparisons of those with and with-out a family history of alcoholism are reported. Methodological recommendations for the computation of acute tolerance are made. The results suggest new methods for measuring the rate of acquisition of acute tolerance, and suggest areas for future research on tolerance-proneness and risk for alcoholism.