The budding yeast Saccharomyces cerevisiae has been a singularly useful eukaryote for the development of Chemical genomic techniques for use in drug discovery studies. Particularly, yeast genomic methodologies provide a solid foundation for high-throughput drug target identification. The success of genomic profiling in budding yeast led to the use of chemical genomics approaches in higher eukaryotic systems. In the present overview, the focus was principally on high-throughput chemical genomic technologies that are advancing the utility of yeast in the drug development research. This led to the review of chemical genomic technologies in other biological systems and the applications of drug synergy in pharmacological research. Finally, the development of genome-wide drug screening was reviewed in the context of drug synergy strategies for discovering novel combinatorial therapies.