The genetic material in humans contains approximately 6 billion base pairs in the nuclear genome and 16,569 base pairs in the mitochondrial genome [1-3]. In some cases the difference between a healthy and a sick individual consists in only one nucleotide. Thus, it is evident that the pristine replication of the genome is a key event in the avoidance of mutations and therefore diseases. Although it is generally believed that DNA is an inert molecule, it contains reactive groups that are exposed to a multitude of chemical agents like Reactive Oxidative Species (ROS), xenobiotic compounds, and UV light which can react with DNA to form adducts that compromise its coding potential. For instance, it is estimated that a mammalian genome suffers close to 100,000 abasic sites per day [4, 5]. In general, replicative DNA polymerases are responsible for maintaining the integrity of the genome during it replication, family X polymerases are important in DNA repair mechanisms, and Translesion Synthesis DNA polymerases ensure the faithful replication across from DNA lesions. This revision attempts to briefly summarize the role of human template dependent DNA polymerases involved in replication, DNA repair, and lesion bypass.