Schistosomes are agents of Schistosomiasis, a major Neglected Tropical Disease (NTD) that affects more >250 million people worldwide. With two separate genetically-determine sexes schistosomes are the exception among flatworms, which are largely hermaphrodites. Male and female worms undergo separate but concurrent sexual differentiation of their gonads and somatic tissues that eventually allows intersexual pairing, a critical step for egg production. This is a key but poorly understood process in early intra-mammalian development of schistosomes. To tackle this knowledge gap, we used functional genomics in tandem with cutting-edge molecular tools and focused on two critical developmental transitions: (1) the cercaria–schistosomulum, i.e. from free-living infectious larva to the first intra-mammalian parasitic stage; (2) sexually monomorphic–dimorphic intra-mammalian developmental stages. For (1), single cell transcriptomics of female or male monomorphic cercariae and two-day old schistosomula revealed sex-biased expression across different cell clusters. For (2), the timing of sexual dimorphism was established in vivo, by morphological analysis and confocal imaging of parasites, and preliminary single cell RNA-seq data identified tentative cell populations underlying this sexual transition. We also developed culture systems for in vitro study of schistosome sexual differentiation and explore long term gene silencing protocols including genome editing. ‘Omics’ approaches coupled with cutting-edge cellular and molecular technologies, will shine new light on schistosome biology and help to expose targets for novel control strategies of this major NTD.