Abstract Based on prior and current experimental results, a hypothesis is presented, that the most effective antineoplastic agents are those agents that modify directly or indirectly the interaction between cells. We also propose that the in vitro assays for antitumor agents in use today may select for unnecessarily toxic agents. Previous results from this laboratory indicated that the antitumor activity of the diacridines correlates best with their effect on the plasma membrane, despite the fact that the prominent biochemical site of action of the diacridines is the inhibition of nucleic acid metabolism. A method has been developed that permits the sensitive determination of the permeability of cells in culture, as well as changes in the intracellular acid-soluble and acid-insoluble nucleic acid pools. The evidence indicates that P-388 cells normally extrude acid-soluble components into the medium, that the diacridines attach to the plasma membrane, alter the degree of extrusion of acid-soluble components of the cells, and modify the intracellular levels of newly synthesized nucleic acids. The present study, performed with four selected diacridines, shows that the diacridines affect these parameters to varying degrees.