Metal complexes have been the subject of numerous investigations in oncology but, despite the plethora of newly synthesized compounds, their precise mechanisms of action remain generally unknown or, for the best, incompletely determined. The continuous development of efficient and sensitive techniques in analytical chemistry and molecular biology gives scientists new tools to gather information on how metal complexes can be effective toward cancer. This review focuses on recent findings about the anticancer mechanism of action of metal complexes and how the ligands can be used to tune their pharmacological and physicochemical properties.