For decades, the discovery of antiparasitics was dominated by whole-organism screening of intact parasite organisms or surrogate parasite models, such as Caenorhabitis elegans, using in vivo animal models or in vitro parasite assays, the latter also known as phenotypic screening. Molecular target-based screening played only a minor role, if at all. While publications using phenotypic screening are abundant in the literature, publications of successful, marketed, antiparasitic drugs discovered using the molecular target-based approach are scarce. This approach, therefore, is often perceived as less relevant for antiparasitic drug discovery than the two other approaches. However, antiparasitics belonging, for example, to the isoxazolines, bispyrazoles, depsipeptides or praziquantel (PZQ) derivatives, imposingly demonstrate the value of this approach, when wisely used in a cooperative manner with phenotypic screening.