Just as homology can trigger a chain of events as described in many of the chapters of this volume, sometimes a lack of homology causes a crisis of a different sort. So it is for the single X chromosome in XY males in many species. Divergent sex chromosome pairs, such as the X and Y chromosomes in mammals and in fruit flies, are thought to have evolved from homologous autosomes. During evolution, the Y chromosome has retained little coding capacity, leaving the male with reduced gene dosage for many functions encoded by the X chromosome. In this chapter we focus on dosage compensation in Drosophila, in which most X-linked genes are upregulated by a male-specific ribonucleoprotein complex. This complex is thought to recognize the X chromosome through approximately 35 dispersed chromatin entry sites and then spread in cis to dosage compensate most genes on the X chromosome.