The amino-terminus of eucaryotic DNA topoisomerase I and the carboxy-terminus of eucaryotic DNA topoisomerase II contain sequences that are enriched in charged amino acid residues, hyper-sensitive to protease digestion, not required for the in vitro topoisomerase activities, able to tolerate insertion and deletion mutations, and thus may have a disordered structure. In an interesting contrast to the catalytically essential core domain, the sequences in these terminal hydrophilic domains are not conserved among the topoisomerases from different species. However, many lines of evidence, including those presented here, demonstrate that the topoisomerase tail domains have critical intracellular functions. The biological functions of the amino-terminus of topoisomerase I include the nuclear import and targeting to the transcriptionally active loci. The carboxy-terminus of topoisomerase II also contains the sequences necessary for nuclear localization and possibly sequences necessary for other critical functions.