The development of new strategies for cancer therapeutics is indispensable for the improvement of standard protocols and the creation of other possibilities in cancer treatment. Yeast models have been employed to study numerous molecular aspects directly related to cancer development, as well as to determine the genetic contexts associated with anticancer drug sensitivity or resistance. The budding yeast Saccharomyces cerevisiae presents conserved cellular processes with high homology to humans, and it is a rapid, inexpensive and efficient compound screening tool. However, yeast models are still underused in cancer research and for screening of antineoplastic agents. Here, the employment of S. cerevisiae as a model system to anticancer research is discussed and exemplified. Focusing on the important determinants in genomic maintenance and cancer development, including DNA repair, cell cycle control and epigenetics, this review proposes the use of mutant yeast panels to mimic cancer phenotypes, screen and study tumor features and synthetic lethal interactions. Finally, the benefits and limitations of the yeast model are highlighted, as well as the strategies to overcome S. cerevisiae model limitations.