In this chapter, we would like to highlight the possible connections between DNA polymerases, the main enzymes in DNA metabolism, and human diseases, also critically evaluating those cases where the experimental data are not fully convincing. To this aim, we will first give a short overview of the three main DNA metabolic events, namely replication, repair and recombination, as well as of the checkpoint pathways acting in response to DNA damage. Besides a role in replication of the genome, DNA polymerases also have fundamental functions in other aspects of DNA metabolism, such as DNA repair, DNA recombination, translesion DNA synthesis and cell cycle checkpoint. In the last 10 years, numerous novel DNA polymerases have been revealed, but their exact cellular functions still await clarification. This review summarizes the known eukaryotic DNA polymerases and their relationships with human diseases.