Our understanding of quantitative traits and their evolution relies on our ability to identify and characterize those sequences changes that are functional and affect phenotypes of interest. Identification of even a single gene that contributes to a complex trait has for a long time been a significant challenge. Yet complex traits are defined by the fact that they are the product of multiple genes with effects that depend on both the genetic and environmental background in which they function. We are combining high-throughput experimental and computational methods to identify functional polymorphism in yeast. Experimental methods include linkage analysis, association studies and quantitative complementation. Computational methods make use of the diverse set of both closely and distantly related yeast genomes in order to identify SNPs that disrupt functionally conserved sequences, ultimately at single-nucleotide resolution.