Many cloned regions of the Drosophila genome show minimal variation between strains in overall sequence arrangement. While restriction site polymorphisms occur and the location of transposable elements may vary from one strain to another, such changes appear to be relatively minor variations superimposed on overall genome stability. In contrast to this general situation, we describe here a segment of the X chromosome that is highly polymorphic in four strains of D. melanogaster and in D. simulans. The strains differ in the presence and extent of a short duplication and the presence of repetitive DNA. These results suggest that different regions of the genome may be subject to different evolutionary constraints, with some regions being particularly prone to extensive changes, even within a single species.