Cattle infected with the tick-borne protozoan, Theileria annulata, usually undergo severe morbidity, and mortality ensues in a high proportion of animals. However, we have shown that a Bos indicus breed, the Sahiwal, which originates in a T. annulata endemic area, is more resistant to the parasite. Although Sahiwals become infected, the breed exhibits fewer clinical signs and recovers from a dose of parasite which is fatal in the Holstein B. taurus breed. The Sahiwals have a significantly lower fever response, and lower levels of parasite than the Holsteins. One unusual feature of this disease is the production of acute phase proteins (APP), indicating that the parasite induces high systemic levels of pro-inflammatory cytokines. In the Holsteins there is prolonged production of the APP, alpha1-glycoprotein, which, in contrast, is only slightly elevated in the Sahiwals. As the parasite infects macrophages (mphi), our hypothesis is that the Sahiwals can control the excessive production of pro-inflammatory cytokines in response to infection, and that this control is expressed at the level of the mphi. We thus reasoned that the genes underlying the observed difference in resistance to tropical theileriosis, might be identified by investigating gene expression differences in mphi from both breeds. It is possible that relevant polymorphisms might in themselves result in gene expression differences, so initially we targeted likely candidates. However, we detected no differences in expression of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta) or IL-6, in infected mphi. As it is more likely that polymorphisms in candidate genes influence the expression of other genes involved in interrelated pathways, we undertook a more global approach. We designed a bovine mphi specific cDNA microarray, which contains representatives of 5000 different genes expressed in mphi, and investigated the transcriptional responses of mphi from both breeds in response to a variety of stimuli, including infection with T. annulata. Our results indicate that there are fundamental differences in gene expression in mphi from both breeds in the way they respond to infection, and even in their pre-infection resting state.