In many taxa, males and females have unequal ratios of sex chromosomes to autosomes, which has resulted in the invention of diverse mechanisms to equilibrate gene expression between the sexes (dosage compensation). Failure to compensate for sex chromosome dosage results in male lethality in Drosophila . In Drosophila , a male-specific lethal (MSL) complex of proteins and noncoding RNAs binds to hundreds of sites on the single male X chromosome and up-regulates gene expression. Here we use population genetics of two closely related Drosophila species to show that adaptive evolution has occurred in all five protein-coding genes of the MSL complex. This positive selection is asymmetric between closely related species, with a very strong signature apparent in Drosophila melanogaster but not in Drosophila simulans . In particular, the MSL1 and MSL2 proteins have undergone dramatic positive selection in D. melanogaster , in domains previously shown to be responsible for their specific targeting to the X chromosome. This signature of positive selection at an essential protein–DNA interface of the complex is unexpected and suggests that X chromosomal MSL-binding DNA segments may themselves be changing rapidly. This highly asymmetric, rapid evolution of the MSL genes further suggests that misregulated dosage compensation may represent one of the underlying causes of male hybrid inviability in Drosophila , wherein the fate of hybrid males depends on which species' X chromosome is inherited.