Schistosomiasis, caused mainly by Schistosoma japonicum, S. mansoni, and S. hematobium, remains one of the most prevalent and serious parasitic diseases worldwide. The blood flukes have a complex life cycle requiring adaptation for survival in fresh water as free-living forms and as parasites in snail intermediate and vertebrate definitive hosts. Functional genomics analyses, including transcriptomic and proteomic approaches, have been performed on schistosomes, in particular S. mansoni and S. japonicum, using powerful high-throughput methodologies. These investigations have not only chartered gene expression profiles across genders and developmental stages within mammalian and snail hosts, but have also characterized the features of the surface tegument, the eggshell and excretory-secretory proteomes of schistosomes. The integration of the genomic, transcriptomic, and proteomic information, together with genetic manipulation on individual genes, will provide a global insight into the molecular architecture of the biology, pathogenesis, and host-parasite interactions of the human blood flukes. Importantly, these functional genomics analyses lay a foundation on which to develop new antischistosome vaccines as well as drug targets and diagnostic markers for treatment and control of schistosomiasis.