Identifying the genetic basis of natural variation in genome-wide gene expression is a daunting task, yet central to characterizing the potential evolutionary impact of gene expression polymorphism. In this issue, Brown et al. reveal the genetic variation that underlies a significant portion of the gene expression polymorphism that segregates in a natural isolate of the wine and bread yeast Saccharomyces cerevisiae. That polymorphism is shown to be associated with a single nucleotide insertion. Interestingly, the major expression polymorphism is not caused by an insertion in a cis-regulatory region or in a transcription factor, but in a homonucleotide repeat within the coding sequence of SSY1, which encodes an amino acid sensor. The expression polymorphism, perhaps unsurprisingly, is also environment-dependent and leads to differential fitness across environments. The result calls for a deeper consideration within molecular ecological genomics of the gene-by-environment interactions that lead to differential gene expression. The finding also calls for further data, clarifying the kinds of genetic variation that constitute gene expression polymorphism between individuals in natural populations.