Systematic analysis of Saccharomyces cerevisiae metabolic functions and pathways has been the subject of extensive studies and established in many aspects. With the reconstruction of the yeast genome-scale metabolic (GSM) network and in silico simulation of the GSM model, the nature of the underlying cellular processes can be tested and validated with the increasing metabolic knowledge. GSM models are also being exploited in fundamental research studies and industrial applications. In this chapter, the principle concepts for construction, simulation and validation of GSM models, progressive applications of the yeast GSM models, and future perspectives are described. This will support and encourage researchers who are interested in systemic analysis of yeast metabolism and systems biology.