The accumulation of amino acid and dipeptide derivatives of DNR has been studied in vitro on L1210 cells. Only Leu-DNR reaches accumulation levels close to DNR, while Val-DNR, Ile-DNR, and Leu-Leu-DNR reach intermediate values. Intracellular DNR was found when the L1210 cells were incubated in the presence of DNR, Leu-Leu-DNR, Leu-Ala-DNR, and Leu-DNR. The cytostatic activity of the derivatives in vitro on L1210 cells cannot be correlated with their uptake or conversion into DNR. At equitoxic doses given iv on the iv inoculated form of L1210 leukemia, all the derivatives are less active than DNR. When given iv on the sc inoculated L1210 leukemia, Leu-DNR, Ala-Leu-DNR and Leu-Leu-DNR are much more active than DNR with a striking increase in ILS and reduction of tumor progression. The superiority of those compounds could be due to their greater hydrophobicity and to their hydrolysis in situ by enzymes secreted by tumor cells or present on the tumor cells surface.