Understanding of the tick–host–pathogen interface has increased dramatically in recent years and will continue to benefit from tick salivary gland transcriptome analysis, proteomics, functional genomics and the first tick genome project. Ticks modulate host haemostasis, pain/itch responses, wound healing and immune defences (Wikel, 1996, 1999; Schoeler & Wikel, 2001; Brossard & Wikel, 2004; Nuttall & Labuda, 2004). Salivary gland genes responsible for these activities are being identified (Valenzuela, 2004; Ribeiro et al., 2006; Alarcon-Chaidez, Sun & Wikel, 2007). Pharmacologically active compounds have been identified in insect and tick salivary glands and their biological activities established (Ribeiro, 1995a, b, 2004; Steen, Barker & Alewood, 2006). In addition to facilitating blood-feeding, these molecules are increasingly recognized as important factors in transmission and establishment of tick-borne infectious agents (Schoeler & Wikel, 2001; Brossard & Wikel, 2004). The biological activities of these molecules can be exploited for development of novel vector and transmission blocking vaccines. Characterizing the immunobiology of the dynamic interactions of the tick–host–pathogen interface is important for understanding infectious agent transmission, innate and specific acquired immune responses developed to the vector and to the pathogen, and for vaccine design. In the following sections, we address current knowledge in key aspects of tick immunobiology.