Parasite-driven dysfunctional adaptive immunity represents an emerging hypothesis to explain the chronic or persistent nature of parasitic infections, as well as the observation that repeated exposure to most parasitic organisms fails to engender sterilizing immunity. This review discusses recent examples from clinical studies and experimental models of parasitic infection that substantiate the role for immune dysfunction in the inefficient generation and maintenance of potent anti-parasitic immunity. Better understanding of the complex interplay between parasites, host adaptive immunity, and relevant negative regulatory circuits will inform efforts to enhance resistance to chronic parasitic infections through vaccination or immunotherapy.