Soluble egg antigen (SEA) and excretory-secretory (ES) products of the egg of Schistosoma mansoni contain a glycosylated T2 family ribonuclease termed omega-1 (ω1). Following release from the egg ω1 instructs antigen presenting cells to induce naive CD4+ T cells to mature into T helper 2 effectors that, in turn, establish the Th2 immunological phenotype characteristic of schistosomiasis. Here schistosome eggs were either transiently exposed to recombinant Cas9 complexed with a synthetic guide RNA (sgRNA) of 20 nt complementary to exon 1 of ω1 by electroporation or transduced with pseudotyped lentivirus encoding Cas9 and this sgRNA. Subsequently some eggs also were transduced with a single stranded oligodeoxynucleotide donor transgene that coded for six stop codons, flanked by 50 nt-long 5′- and 3′-homology arms matching the predicted Cas9-catalyzed double stranded break (DSB) within ω1. CRISPResso analysis of amplicons spanning the predicted DSB revealed ~6% of the reads (total reads 2×61620×106) were mutated by insertions, deletions and/or substitutions, with an efficiency for homology directed repair of 0.18% insertion of the donor transgene. ω1-encoding mRNAs were reduced > 80%, and soluble egg antigen (SEA) from ω1-mutated eggs exhibited markedly reduced ribonuclease activity, indicative that programmed Cas9 cleavage had mutated the ω1 gene. Following tail vein injection of schistosome eggs into BALB/c mice, the volume of pulmonary granulomas surrounding wild type eggs was 18-fold greater than ω1-mutated eggs, 6.21×10 −2 ± 1.61×10 −3 vs. 0.34×10 −2 ± 0.12×10 -4 mm 3 , respectively. In parallel, whereas wild-type SEA polarized Th2 cytokine responses including IL-4 and IL-5 in human monocyte/T cell co-cultures, significantly reduced levels of these cytokines followed the exposure to ω1-mutated SEA. In overview, programmed genome editing was active and facile in schistosomes, Cas9-catalyzed chromosomal breakage was repaired by HDR and/or NHEJ, and mutation of ω1 impeded the capacity of schistosome eggs to drive Th2 polarization and to provoke formation of pulmonary circumoval granulomas. These findings demonstrated for the first time the utility of CRISPR/Cas9-based genome editing for functional genomics for schistosomes.