Peptide nucleic acids (PNA) were originally conceived and designed as sequence-specific DNA binding reagents targeting the DNA major groove in analogy to triplex-forming oligonucleotides. However, instead of the sugar-phosphate backbone of oligonucleotides PNA was designed with a pseudopeptide backbone (1). Once synthesized, it was apparent that PNA oligomers based on the aminoethylglycin backbone with acetyl linkers to the nucleobases (see Fig. 1) are extremely good structural mimics of DNA (or RNA), being able to form very stable duplex structures with Watson-Crick complementary DNA, RNA (or PNA) oligomers (2, 3, 4). It also quickly became clear that triplexes formed between one homopurine DNA (or RNA) strand and two sequence complementary PNA strands are extraordinarily stable. Furthermore, this stability is the reason why homopyrimidine PNA oligomers when binding complementary targets in double-stranded DNA do not do so by conventional (PNA-DNA2) triplex formation, but rather prefer to form a triplex-invasion complex in which the DNA duplex is invaded by an internal PNA2-DNA triplex (see Fig. 2) (5,6). This type of binding is restricted to homopurine/homopyrimidine DNA targets in full analogy to dsDNA targeting by triplex forming oligo nucleotides (see Fig. 3). However, other binding modes for targeting dsDNA is available for PNA (7) of which the double duplex invasion (8) is believed to become very important, because it allows the formation of very stable complexes at mixed purine-pyrimidine targets as long as they have a reasonable (∼ 50%) A/T content (see Fig. 4). The DNA/RNA recognition properties of PNA combined with excellent chemical and biological stability and tremendous chemical-synthetic flexibility has made PNA of interest to a range of scientific disciplines ranging from (organic) chemistry to biology to medicine