A newly discovered DNA motif determined by its sequence and shape, named PionX (pioneering sites on the X), allows the dosage compensation machinery in Drosophila melanogaster to distinguish X chromosomes from autosomes. In fruitflies, the male-specific lethal dosage compensation complex (MSL-DCC) doubles gene expression from the single male X chromosome. Using an in vitro DNA immunoprecipitation assay, Villa et al. showed that MSL-DCC recognizes the X chromosome at specific sites through one of its components, MSL2. Deletion of various protein domains revealed that MSL2 interacts with DNA through two domains. A subset of genomic regions required a functional CXC domain for binding, and these sites were enriched on the X chromosome. Sequence analyses comparing CXC-dependent and -independent binding sites for MSL2 yielded two distinct motifs. Further analyses confirmed that MSL2 relies on both DNA sequence and structure to identify its binding sites.