When polymorphism and divergence data are available for multiple loci, extended forms of the McDonald-Kreitman test can be used to estimate the average proportion of the amino acid divergence due to adaptive evolution--a statistic denoted alpha. But such tests are subject to many biases. Most serious is the possibility that high estimates of alpha reflect demographic changes rather than adaptive substitution. Testing for between-locus variation in alpha is one possible way of distinguishing between demography and selection. However, such tests have yielded contradictory results, and their efficacy is unclear. Estimates of alpha from the same model organisms have also varied widely. This study clarifies the reasons for these discrepancies, identifying several method-specific biases in widely used estimators and assessing the power of the methods. As part of this process, a new maximum-likelihood estimator is introduced. This estimator is applied to a newly compiled data set of 115 genes from Drosophila simulans, each with each orthologs from D. melanogaster and D. yakuba. In this way, it is estimated that alpha approximately 0.4+/-0.1, a value that does not vary substantially between different loci or over different periods of divergence. The implications of these results are discussed.