Identifying the genetic basis of adaptive phenotypes can be a significant step towards understanding how that phenotype evolved. With the increased availability of interspecific molecular data, an approach to uncover such genes has been to search for signatures of adaptive evolution at the molecular level. Many analyses have adopted a candidate gene approach, focusing on genes with important developmental roles. One such candidate gene is ASPM, which is involved in neurogenesis and associated with major neurological disorders [1]. The molecular evolution of ASPM has been investigated for a decade (see electronic supplementary material, table S1), under the hypothesis that it contributes to primate brain evolution. A recent study by Xu et al.[2] extends the taxonomic scope by demonstrating that ASPM evolved adaptively in cetaceans. However, descriptive studies of patterns of selection are now being supplanted by those that explicitly test for gene -phenotype associations. Using such an approach, we find that Xu et al.'s conclusion that ASPM is linked to increases in cetacean encephalization quotient (EQ), a measure of relative brain size, is not supported. We highlight developments in the analysis of molecular data and phylogenetic methods that are capable of resolving major issues in functional gene -phenotype coevolution, which we hope will provoke discussion and aid future studies.One approach for making gene -phenotype associations is to test for shifts in selection pressure acting on a gene in taxa that display the phenotype of interest. This frequently involves comparing estimates of dN/dS, a measure of the strength of selection acting on a protein-coding gene, using a range of tests implemented in software such as PAML (see electronic supplementary material, table S2) [3]. The results of these tests can be influenced by the nature of the data and, in particular, require sufficient evolutionary variation to make reliable estimates. Data with few substitutions or from a restricted number of taxa can lead to spurious results. These effects may be evident in Xu et al.'s analysis [2]. First, they suggest that a high proportion of branches in the cetacean phylogeny have an elevated dN/dS, which they interpret as evidence of increased positive selection, but do not perform explicit tests of this hypothesis. Further analysis (see the electronic supplementary material) suggests that none of these values are significantly greater than one, the threshold for accepting adaptive evolution. The apparent elevation in dN/dS is likely to be influenced by the low number of substitutions on short branches. This problem is particularly strong for cetaceans, which have low substitution rates [4]. Second, it is suggested that positive selection is limited to mammalian orders with high EQs. However, this result is likely to be influenced by sampling bias, and inclusion of further taxa provides evidence for positive selection across mammals (see the electronic supplementary material). Identifying robust shifts in selection pressur...