The development of vaccines to protect against parasites is difficult, in large part due to complex host-parasite interactions that have evolved over millennia. Parasitic factors such as antigenic variation and host factors such as age, transmission intensity, and genetic influences are all thought to contribute to the limited efficacy of parasite vaccines. A developing theme in field studies investigating antiparasitic immunity is the emergence, establishment, and maintenance of immunoregulatory networks that shape the immune responses to new infections, as well as vaccines, thereby influencing disease outcome. In this review, we will examine why parasite vaccine candidates perform poorly in target populations and, in particular, the role of immunoregulatory networks in influencing antimalarial immunity and vaccine efficacy. We will focus our discussion on malaria, the most important parasitic disease of humans, but also highlight the broader impact of immunoregulatory networks on vaccine efficacy.