For decades after its discovery, genomic DNA was believed to exist only as a right-handed, double helix known as B-DNA.  Its sole functions were to serve as a template for RNA synthesis or as a template for the production of identical duplexes during chromosome replication.  These core beliefs were shaken by the discovery that DNA is covalently modified and packaged into chromatin, and that the molecule can form an enormous variety of non-B alternative structures, including cruciforms, a left-handed helix, three- and four-stranded helices, and slip-strand configurations.  Transient denaturation of the duplex during all major DNA transactions (replication, transcription, repair and recombination) requires chromatin modifications and promotes dynamic transitions to non-B DNA structures.  Furthermore, repetitive DNA sequences, which are highly over-represented in genomic DNA, are particularly prone to structural transitions.  Studies conducted in many labs worldwide have confirmed that structural transitions are not only central to normal functions of the genome, but also are responsible for occasional malfunctioning that leads to a disease state.  The most striking example is expansion of structure-prone DNA repeats, which is responsible for more than thirty hereditary neurological and developmental diseases.