The expanding world of DNA and RNA

[Display omitted] •Modified nucleotides stabilize and increase the potential functions of DNA and RNA.•Modified nucleotides allow DNA and RNA to adopt protein-like structures.•Hydrophobic and packing forces may be used to expand the potential of DNA and RNA.•Nucleotides with unnatural nucleobases may be used to develop unnatural base pairs.•It is now possible to synthesize and even replicate modified or unnatural DNA in cells. DNA and RNA are remarkable because they can both encode information and possess desired properties, including the ability to bind specific targets or catalyze specific reactions. Nucleotide modifications that do not interfere with enzymatic synthesis are now being used to bestow DNA or RNA with properties that further increase their utility, including phosphate and sugar modifications that increase nuclease resistance, nucleobase modifications that increase the range of activities possible, and even whole nucleobase replacement that results in selective pairing and the creation of unnatural base pairs that increase the information content. These modifications are increasingly being applied both in vitro and in vivo, including in efforts to create semi-synthetic organisms with altered or expanded genetic alphabets.