Understanding genotype-phenotype dependency is a universal aim for all life sciences. While the complete genotype-phenotype relations remain challenging to resolve, metabolic phenotypes are moving within the reach through genome-scale metabolic model simulations. Genome-scale metabolic models are available for commonly investigated yeasts, such as model eukaryote and domesticated fermentation species Saccharomyces cerevisiae, and automatic reconstruction methods facilitate obtaining models for any sequenced species. The models allow for investigating genotype-phenotype relations through simulations simultaneously considering the effects of nutrient availability, and redox and energy homeostasis in cells. Genome-scale models also offer frameworks for omics data integration to help to uncover how the translation of genotypes to the apparent phenotypes is regulated at different levels. In this chapter, we provide an overview of the yeast genome-scale metabolic models and the simulation approaches for using these models to interrogate genotype-phenotype relations. We review the methodological approaches according to the underlying biological reasoning in order to inspire formulating novel questions and applications that the genome-scale metabolic models could contribute to. Finally, we discuss current challenges and opportunities in the genome-scale metabolic model simulations.