The eastern oyster (Crassostrea virginica) is a protandrous hermaphrodite of commercial importance. As with many marine invertebrates, little is known about sex determination and differentiation systems in this species. Such knowledge has important implications not only for understanding the evolution of sex but also for applied questions in aquaculture. In order to examine mechanistic differences in reproductive development between the sexes, we compared the transcriptomes of gonad and mantle tissue from 6 male and 6 female oysters. A total of 7,675 transcripts were differentially expressed between male and female gonads (3,936 and 3,739 up-regulated in males and females, respectively). Transcripts identified include those associated with sex in other invertebrate and vertebrate species such as Dmrt1, SOX-30, bindin, dpy-30, and histone H4 in males and foxl2, vitellogenin, and Bystin in females. GO terms associated with transcripts up-regulated in male gonad include protein modification, reproductive process, and cell projection organization, while RNA metabolic process and amino acid metabolic process were associated with transcripts up-regulated in females. Far fewer transcripts were differentially expressed between male and female mantle tissue, with 87 transcripts up-regulated in females and 16 up-regulated in males. However, 41% of transcripts identified as differentially expressed between mantle tissues were also differentially expressed between male and female gonads including Histone H4 and Bystin. This study represents the first characterization of eastern oyster male and female gonad transcriptomes. We further identify differing expression profiles between male and female mantle tissue, providing evidence for sex-specific functions of the mantle and suggesting this tissue could harbor biomarkers for identifying oyster sex non-destructively.