Hemin (ferric protoporphyrin IX chloride) has been shown to cause strand scission in DNA in a reaction which requires the presence of oxygen and the reducing agent, 2-mercaptoethanol. In model studies, circular supercoiled plasmid DNA is converted within 30 min to the open circle and linear forms. With longer incubation times the DNA is degraded to small pieces. The reaction is markedly influenced by the addition of divalent cations; Mg2+ and Ca2+ inhibit the reaction while the transition metals Co2+, Zn2+, Ni2+, and Cu2+ promote the degradation. These observations are discussed in relation to the role of hemin in the modulation of gene expression during cell differentiation.