Since the initial description of Th1 and Th2 subsets in the 1980s, there has been enormous progress in identifying the molecular events and the transcriptional factors that regulate Th differentiation in response to a specific stimulus (e.g. antigen dose, co-receptors, cytokines). Although TCR cross-linking and engagement of co-stimulatory molecules are necessary for activation of CD4+ lymphocytes, these two events do not appear in themselves to explain Th1/Th2 commitment. Among pathogens, helminths are the main examples of Th2-cell inducers in both humans and experimental models. This review will focus on our recent findings on the requirements for Th2 polarization by the parasitic trematode Schistosoma mansoni. In particular, we will address the ongoing controversy as to whether Th2 development depends on positive vs. negative vs. the absence of signals from antigen-presenting cells. In addition, we will discuss the similarities between the pathways involved in parasite- and allergen-induced Th2 differentiation.