Malaria is possibly the most serious infectious disease of humans, infecting 5–10% of the world's population, with 300–600 million clinical cases and more than 2 million deaths annually. Adaptive immune responses in the host limit the clinical impact of infection and provide partial, but incomplete, protection against pathogen replication; however, these complex immunological reactions can contribute to disease and fatalities. So, appropriate regulation of immune responses to malaria lies at the heart of the host–parasite balance and has consequences for global public health. This Review article addresses the innate and adaptive immune mechanisms elicited during malaria that either cause or prevent disease and fatalities, and it considers the implications for vaccine design.