The present invention provides a nucleic acid molecule encoding a tyrosine-DNA phosphodiesterase (TDP), and a related vector, host cell, polypeptide, antibody, antisense nucleic acid molecule, and ribozyme. Also provided are a method of altering the level of TDP in a cell, tissue, organ or organism, as well as the resulting cell, tissue, organ or non-human organism, as well as a method of identifying a TDP-resistant compound, a method of assessing TDP1 activity in an animal, and a method of assessing the efficacy of a topoisomerase I inhibitor.