Thiosemicarbazones have been explored for their applicability as antitumour agents for half a centure [1]. The enzyme ribonucleotide reductase has been identified as the principal target [2]. In fact, these compounds are the strongest known inhibitors of this enzyme, both in cell-free assays and in intact tumour cells, being several orders of magnitude more effective than hydroxyurea, the first clinically applied ribonucleotide reductase inhibitor. The enzyme that catalyzes the conversion of ribonucleotides to deoxyribonucleotides is produced at the transition from the G1 to the S phase of the cell cycle as a prerequisite for DNA replication and is highly expressed in tumour cells, making it a suitable and well established target for cancer chemotherapy. Herewith I will report on the synthesis of a number of metal complexes with different 4N-substituted thiosemicarbazones allowing for the exploration of structure-activity relationships with regard to the role of the central metal, the metal-to-ligand stoichiometry and the impact of structural modifications of the thiosemicarbazone ligand on antiproliferative activity and RNR inhibition. Particular attention will be paid on the activity and mechanism of action of metal complexes with Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), the most prominent example of this family of compounds that has been extensively studied as a single agent and in combinations with established drugs in phase I and II clinical trials with mixed results. In addition, the synthesis and antiproliferative activity of copper(II) complexes with chiral thiosemicarbazone-proline conjugates will be presented.