Abstract Targeting the cellular Ca2+ channels and pumps that underpin parasite Ca2+ homeostasis may realize novel antihelmintic agents. Indeed, the antischistosomal drug praziquantel (PZQ) is a key clinical agent that has been proposed to work in this manner. Heterologous expression data has implicated an action of PZQ on voltage-operated Ca2+ channels, although the relevant in vivo target of this drug has remained undefined over three decades of clinical use. The purpose of this review is to bring new perspective to this issue by discussing the potential utility of free-living planarian flatworms for providing new insight into the mechanism of PZQ action. First, we discuss in vivo functional genetic data from the planarian system that broadly supports the molecular data collected in heterologous systems and the ‘Ca2+ hypothesis’ of PZQ action. On the basis of these similarities we highlight our current knowledge of platyhelminth voltage operated Ca2+ channels, their unique molecular pharmacology and the downstream functional PZQ interactome engaged by dysregulation of Ca2+ influx that has potential to yield novel antischistosomal targets. Overall the broad dataset underscores a common theme of PZQ-evoked disruptions of Ca2+ homeostasis in trematodes, cestodes and turbellarians, and showcases the utility of the planarian model for deriving insight into drug action and targets in parasitic flatworms.