Although there are some obvious differences between the X chromosome and the autosomes—such as the X chromosome being present in only one copy in males—the two types of chromosome are remarkably similar in their cytological appearance and gene density [1]. Genomic and transcriptomic studies of Drosophila, however, have revealed two major differences in gene content between the X chromosome and the autosomes. First, there is an excess of functional, duplicate genes that have moved from the X chromosome to the autosomes (Figure 1A) [2]. Second, there is a paucity of genes with male-biased expression on the X chromosome (Figure 1B) [3]. A hypothesis that could explain these observations was proposed by Betran and colleagues in 2002 [2] and is based on the phenomenon of meiotic sex chromosome inactivation (MSCI, see below). Since then, there has been controversy about whether or not MSCI occurs in Drosophila and, if it does, what role it plays in shaping the gene content of the X chromosome. In this issue of PLoS Genetics, Vibranovski et al. [4] present a detailed analysis of gene expression across three stages of Drosophila spermatogenesis. Their results support the occurrence of MSCI and suggest that its effect on germline expression of X-linked genes promotes the selective maintenance of autosomal duplicates arising from X-linked genes. Figure 1 The X chromosome and autosomes of Drosophila melanogaster differ in retrogene and male-biased gene content.