The resistance of Bos taurus and B. indicus cattle and of their crosses to infestation with the tick Boophilus microplus was assessed by repeated experimental infestation. The assessment was based on the yield of engorged female ticks, the weight of the engorged female, the weight of the eggs laid, and the duration of the parasitic life cycle. Two types of resistance were observed: an acquired resistance which became evident after repeated exposure, and an innate resistance which was present in some animals, never previously exposed, on their first infestation. Acquired resistance was least apparent in purebred B. taurus, but considerable variation in the degree of resistance was observed between individuals within the respective breed groups. When a group of purebred B. taurus (Shorthorns) and a group of B. taurus (Shorthorn) x B. indicus (Zebu) were exposed to natural infestations, the crossbreds were significantly more resistant. Acquired resistance was shown to be associated primarily with the development of a hypersensitivity to the salivary secretion of the tick and was manifested by serous exudation, usually accompanied by a papular reaction, at the site of attachment of the tick. Histological changes in the skin following attachment of the various instars are described. Lesions indicative of an allergic reaction were found only in animals with soma degree of resistance, and consisted of cellular invasion, predominantly eosinophilic, which extended deep into the dermis. In highly resistant cattle, blood histamine concentration reached a peak 48 hr after infestation with larvae and subsided to normal levels 7–8 days later. In susceptible cattle, there was little or no variation in histamine levels during the parasitic life cycle of the tick. In animals with varying degrees of resistance, temporary increases occurred following the larval and nymphal moults. No correlation could be found between skin thickness or sweat gland or sebaceous gland concentrations and the degree of resistance. Some evidence was obtained that it may be possible to induce the hypersensitive state, with consequent reduction in tick burden, by repeated daily subcutaneous injections of 0.5 ml of a 1 in 10 dilution of larval extract. Innate resistance was observed in some B. indicus. The mechanism appeared to persist in subsequent exposures, but its significance was difficult to assess, as some animals manifesting this type of resistance also became hypersensitive.