The programmability of DNA/RNA-based molecular circuits provides numerous opportunities in the field of synthetic biology. However, the stability of nucleic acids remains a major concern when performing complex computations in biological environments. Our solution to this problem is l -(deoxy)ribose nucleic acids ( l -DNA/RNA), which are mirror images (i.e. enantiomers) of natural d -nucleotides. l -oligonucleotides have the same physical and chemical properties as their natural counterparts, yet they are completely invisible to the stereospecific environment of biology. We recently reported a novel strand-displacement methodology for transferring sequence information between oligonucleotide enantiomers (which are incapable of base pairing with each other), enabling bio-orthogonal l -DNA/RNA circuits to be easily interfaced with living systems. In this perspective, we summarize these so-called ‘heterochiral’ circuits, provide a viewpoint on their potential applications in synthetic biology, and discuss key problems that must be solved before achieving the ultimate goal of the engineering complex and reliable functionality.