Ribozymes are RNA molecules that can catalyze biochemical reactions including polymerization of other RNA molecules. Their discovery provided support to the 'RNA world' hypothesis, which postulates that life based on RNA might have been the first to emerge on Earth, given RNA's ability to store information like DNA and to catalyze biochemical reactions like protein enzymes. However, all polymerization reactions by ribozymes observed so far occur only in a homochiral system, and the nonenzymatic polymerization of RNA is halted by the incorporation of ribonucleotides of the opposite handedness. This enantiomeric cross-chiral inhibition created a quandary because both D-and L-RNA probably coexisted in prebiotic Earth, before D-RNA affirmed itself as the dominant enantiomer. Hence, it has remained puzzling how ribozymes could have overcome the chiral inhibition in the presence of both enantiomers as substrates. Now, Sczepanski and Joyce show that polymerization of both D- and L-RNA may have emerged together, thanks to ribozymes capable of cross-chiral RNA polymerization. By using in vitro evolution, they generated an 83-nucleotide D-ribozyme that could catalyze ligation of L-RNA mono- or oligonucleotides on an L-RNA template. Similarly, the mirror-image L-ribozyme was able to catalyze the reaction of D-enantiomers. Both D- and L-ribozymes were not subject to cross-chiral inhibition, because they could perform the catalysis in the presence of a mixture of substrates and templates of both handed versions. The cross-chiral ribozyme catalyzed the ligation a million times faster than the noncatalyzed reaction, recognized the substrates on the basis of tertiary, sequence-independent contacts and joined substrates regardless of their length, provided that they were bound to a complementary template. Notably, the D-ribozyme could assemble L-oligonucleotides into a fully functional mirror copy of itself, also capable of cross-chiral catalysis. Why homochiral ribozymes eventually emerged remains an open question, and the authors speculate that an achiral polymer able to catalyze both D- and L-RNA might have preceded RNA-based life. (Nature 515, 440–442, 2014)