Hairpins represent the dominant secondary structure element in RNA. Certain sequences are found with exceptional frequency in many RNAs and are characterized by exceptionally high thermodynamic stability. Stable RNA hairpins define nucleation sites for folding, determine tertiary interactions in RNA enzymes, protect mRNAs from degradation, and are recognized by RNA-binding proteins. The structures of several stable DNA and RNA hairpins have revealed networks of stabilizing interactions within the hairpin loop: non-Watson-Crick base pairs and base-phosphate and base-sugar contacts. The unusual stability of these structural elements can be used to stabilize RNA and DNA structures and to protect antisense oligonucleotides and mRNAs against exonucleolytic degradation.