Expansion of sequencing efforts to include thousands of genomes is providing a fundamental resource for determining the genetic diversity that exists in a population. Now, high-throughput approaches are necessary to begin to understand the role these genotypic changes play in affecting phenotypic variation. Saccharomyces cerevisiae maintains its position as an excellent model system to determine the function of unknown variants with its exceptional genetic diversity, phenotypic diversity, and reliable genetic manipulation tools. Here, we review strategies and techniques developed in yeast that scale classic approaches of assessing variant function. These approaches improve our ability to better map quantitative trait loci at a higher resolution, even for rare variants, and are already providing greater insight into the role that different types of mutations play in phenotypic variation and evolution not just in yeast but across taxa.