The synthesis of 5 new psoralen derivatives is described. 4''-Hydroxymethyl-4,5'',8-trimethylpsoralen, 4''-methoxymethyl-4,5'',8-trimethylpsoralen and 4''-aminomethyl-4,5'',8-trimethylpsoralen hydrochloride, are characterized with respect to their photoreactivity with DNA and RNA. They are superior to 4,5'',8-trimethylpsoralen and 8-methoxypsoralen, the 2 commonly used psoralens, in their abilities to saturate the photoreactive sites on DNA and RNA without repeated addition of reagent. A simplified mechanism for the photoreaction of psoralens with nucleic acids is presented and provides a basis for understanding the superior properties of these compounds. The compounds have superior reactivity not only with isolated DNA and RNA but also in viruses and in cells. Psoralens are shown for the 1st time to cross-link RNA double helices.