Despite great advances in understanding the molecular etiology of cancer and neurodegeneration, therapeutic strategies against these diseases are still largely lacking. Hence, acceleration of the discovery of new therapeutic agents against these pathologies is of enormous interest. This review is focused on the role of multi-faceted and expanding yeast cell-based systems in the search for new drugs and therapeutic targets in cancer and neurodegeneration. Though the obvious limitations of using a microorganism to address human diseases, when used in the early phase and with complementary mammalian systems, it can have a tremendous impact in the discovery of new therapeutic opportunities. In this review, many evidence are provided demonstrating the valuable contribution of yeast in this area. Additionally, several yeast target-based drug screening approaches based on a readily screenable phenotype on genomic technologies increasingly oriented towards genetic and chemical high-throughput analysis are addressed. Altogether, with this review, we intend not only to recognize previous successes and ongoing work in this area, but also to point out new opportunities that may be of interest for yeast as a model organism and as a powerful system in the discovery of new lead compounds that have the potential to become novel drugs in cancer and neurodegeneration.