During cell growth and proliferation eukaryotic cells are exposed to many kinds of adverse agents, including exogenous agents such as chemical and physical agents, as well as to endogenous agents like reactive oxygen species (ROS) from oxidative metabolism or electron transport chain that can all result in damage to DNA. In yeast, high intracellular ROS levels pose a significant threat to cellular integrity and can lead to mitochondrial DNA damage, impairment of mitochondrial respiration, reduction of oxygen consumption inhibition of two key glycolytic enzymes, GAPDH and PYK. The metabolic flux does not shunt to the late stage of glycolysis, Krebs cycle, and through electron transport chain where a large amount of A TP are generated per glucose molecule, but diverts to the early stage of glycolysis, namely to the pentose phosphate pathway, hexosamine biosynthesis, and finally to glycogen and trehalose synthesis. Glycogen and trehalose act as readily mobilized storage in the form of glucose for survival of cells and maintenance of cellular energy. To handle such kinds of DNA damage, yeast cells have evolved a number of cellular mechanisms or responses including DNA damage checkpoints, cell cycle arrest, transcriptional program activation, stimulation of DNA repair, tolerance of DNA damage and initiation of apoptosis. These cellular defense mechanisms are regulated by specific genes in which their role and function are similar to those found in mammanlians. Thus, in this review, the authors discuss DNA mutating agent, DNA damage repair and cellular defense mechanisms, and the homology of function between human and yeast genes, as well as the use of yeast cell as a model organism for cell cycle and biochemital pathway study, new drug discovery, and cancer research.