The effects of the protein cesalin were studied to determine the site of its toxic action in KB cells for which the ID50 is 0.9 pg/ml. Several effects have been noted: (i) respiration in KB cells was reduced by greater than 50% within 1 h after cesalin addition, which could not be explained on the basis of mitochondrial damage or from elevated intracellular ATP levels, since these did not rise significantly until about 3 h after cesalin addition; (ii) both DNA and RNA synthesis were inhibited, starting about 3 h after addition of cesalin to KB cells, but the transport of nucleosides and amino acids does not appear to be affected; (iii) no decrease is observed in protein synthesis for at least 5 to 6 h; (iv) cesalin can inhibit DNA synthesis and mitotic division independently of one another. The interaction of cesalin with the cell surface is rapid and after 5 min at 37 degrees C less than 10% of treated cells can be rescued by addition of excess antiserum to cesalin. The cell surface receptors are exposed throughout the cell cycle and the toxicity of cesalin is not restricted to a particular phase of this cycle.