Unstable transmission of repeating segments in genes is now recognized as a new class of mutations causing human disease. Genetic instability observed in disease is termed an "expansion mutation" when the mutation is an increase in the copy number of a repeated unit, commonly a di- or trinucleotide. While the expansion mutation is well characterized in disease, the mechanism by which expansion occurs is not clear. This article focuses on physical properties of expansion at repeating nucleotides that may provide clues to the mechanism. Both biochemical and genetic data indicate that DNA structure is part of the mechanism and the underlying cause for expansion.