Wild mammals in Africa mostly have high levels of innate resistance to haemoparasites and the tick vectors that transmit them. Occasionally though, biotic and abiotic factors combine to alter this relationship and tick-borne disease is diagnosed in wildlife. We postulate an inter-relationship between anthropogenic and natural factors that resulted in wildlife mortality, attributable to disease transmission associated with a gradual build-up of large numbers of ticks. Suppression of grassland fire for 27 years in a distinct ecological unit promoted a gradual expansion of areas covered by tall grass. Changes in composition of the pasture led to improved tick survival, which was further boosted by the availability of increasing numbers of a coarse-grazing species and preferred tick host, African buffalo. Alternating climatic cycles then appeared to precipitate an outbreak of tick-borne haemolytic disease by subjecting ticks and their herbivore hosts to ideal conditions (in wet years) followed by starvation and immune suppression (in dry years). Evidence supporting the hypothesis was gathered retrospectively in the present study through systematic sampling of tick density and correlating life stages of ticks to season, grass species and height of the grass sward. Tick host preference was noted by collection from immobilized wild animals and sympatric livestock. A long series of census data confirmed the changing composition of resident wild herbivores in the Ngorongoro Crater. To reduce the tick challenge, prescribed burning of the crater grassland was reintroduced; tick numbers fell rapidly and three years of subsequent monitoring confirmed the success of this strategy.