DNA encodes information in the sequence of the four deoxynucleotides dA, dT, dG, and dC. The key element for information storage and retrieval in this four-letter alphabet involves selective hydrogen bonding in the complementary base pairs dA:dT and dG:dC. Are these universal bases a unique structural solution for the genetic code, or are there other base pairing schemes that can be incorporated into DNA? To address this question, we and others have begun to synthesize and evaluate base pairs with alternate pairing interactions. The ability to generate additional such pairs would not only increase the capacity of DNA for information storage 1 but would also allow the replication of DNA containing novel functional groups. 2 In addition, nucleic acids completely built out of artificial base pairs could lead to novel polymers with interesting chemical and physical properties. Efforts to expand the genetic alphabet have focused largely on two strategies: hydrogen bonding patterns different from those in dA:dT and dG:dC 3 and hydrophobic packing interactions. 4,5 Here we describe a new strategy which is based on the metaldependent pairing of two nucleobases. 6,7 We have designed a base