The genetic code is simple: four bases that form two pairs (A–T and G–C) are used in all of life. Expansion of this code to incorporate unnatural nucleotides and base pairing has been a goal of synthetic biology, as it would open up ways to tailor organisms for directed purposes. Although this has been achieved in proof-of-principle experiments in vitro, stable propagation of an expanded code had not been demonstrated in vivo until now. Floyd Romesberg and colleagues present evidence that two hydrophobic nucleotides, d5SICSTP and dNaMTP, can be added to the medium in which Escherichia coli expressing an exogenous algal nucleotide triphosphate transporter is growing, and that these nucleotides will be incorporated in the genome and are not recognized as lesions by the repair pathway. Consequently, the unnatural-base-pair-containing DNA is replicated, without cell growth being significantly affected.