The genetic basis of many phenotypes of biological and medical interest, including susceptibility to common human diseases, is complex, involving multiple genes that interact with one another and the environment. Despite decades of effort, we possess neither a full grasp of the general rules that govern complex trait genetics nor a detailed understanding of the genetic basis of specific complex traits. We have used a cross between two yeast strains, BY and RM, to systematically investigate the genetic complexity underlying differences in global gene expression and other traits. The number and diversity of traits dissected to the locus, gene, and nucleotide levels in the BYxRM cross make it arguably the most extensively characterized system with regard to causal effects of genetic variation on phenotype. We summarize the insights obtained to date into the genetics of complex traits in yeast, with an emphasis on the BYxRM cross. We then highlight the central outstanding questions about the genetics of complex traits and discuss how to answer them using yeast as a model system.