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Background: Ticks and tick-borne diseases are a global problem and considered as one of the major challenges to livestock health and performance. Ticks affect 80% of the cattle population across the world with an estimated economic loss of USD $20 – 30 billion per/year worldwide. Numerous tick control strategies have been employed in Southern Africa including the application of acaricides. However, development of resistance to chemicals by ticks limits the effectiveness of this control strategy. Breeding for resistance or tolerance offers a complementary approach that is sustainable in the long term. This study aimed to identify genes that mediate immune responses in tick-tolerant Nguni, tick-susceptible Angus, and F2 Nguni X Angus cattle, infested with Amblyomma hebraeum ticks.Methods: Cattle were phenotyped for resistance to Amblyomma hebraeum ticks as determined by the total number of engorged ticks after a period of 10 days. Skin biopsy samples were collected before infestation, defined as day 1- and 10-days post-infestation. RNA was isolated from the skin biopsies and sequenced to identify differentially expressed genes between these two time points in resistant and susceptible animals.Results: Five genes (PHKG1, PHKA1, CAMK21, NOS2, HRC) were significantly differentially expressed between the susceptible and resistant cattle. Four of these five genes were highly expressed (significant) in the susceptible group before tick infestation. CAMK21 was found to be highly expressed in the resistantt group after tick infestation. HRC was found to be highly (significant) expressed in the susceptible group before tick infestation, but only highly expressed in resistant group after tick infestation.Conclusion: This research reports differential gene expression in the skin following tick bites, thus providing preliminary data concerning the underlying mechanisms associated with the immune response.