Polarized migration and spreading of epithelial sheets is important during many processes in vivo, including embryogenesis and wound healing. However, the signaling pathways that regulate epithelial migrations are poorly understood. To identify molecular components that regulate the spreading of epithelial sheets, we performed a screen for mutations that perturb epidermal cell migration during embryogenesis in Caenorhabditis elegans. We identified one mutant (jc5) as a weak mutation in itr-1, which encodes the single inositol 1,4,5-trisphosphate receptor (ITR) in C. elegans. During the migration of the embryonic epidermis, jc5 embryos display defects including misdirected migration or premature cessation of migration. Cells that halt their migration have disorganized F-actin and display reduced filopodial protrusive activity at their leading edge. Furthermore, some filopodia formed by epidermal cells in itr-1(jc5) embryos exhibit abnormally long lifetimes. Pharmacological studies with the inositol 1,4,5-trisphosphate antagonist xestospongin C phenocopy these defects, confirming that ITR function is important for proper epidermal migration. Our results provide the first molecular evidence that movements of embryonic epithelial cell sheets can be controlled by ITRs and suggest that such regulation may be a widespread mechanism for coordinating epithelial cell movements during embryogenesis.