Ticks are blood-feeding ectoparasites that serve as vectors for transmission of diseases such as Lyme borreliosis and tick-borne encephalitis. There are two proteolytic systems in ticks that are essential for the interactions with the host and the transmission of the pathogens: (1) Protease inhibitors from the tick saliva help to disarm the host haemostatic system and alter the inflammatory and host immune responses. (2) Proteases in the tick gut are responsible for digestion of host blood proteins, the ultimate source of nutrients for their growth, development and reproduction. Proteins from both proteolytic systems are increasingly recognized as potential antigens for the development of “anti-tick” vaccines that protect against the ticks and reduce the risk of pathogen transmission. We present structural and functional analysis of the following members of these proteolytic systems: OmC2, a salivary protease inhibitor from the cystatin superfamily, is an immunomodulatory protein that suppresses the host’s adaptive immune response. The crystal structure of OmC2 (2.5 Å) was used to explain its inhibitory specificity against mammalian cysteine cathepsins from several types of immune cells. IRS-2, a salivary protease inhibitor from serpin superfamily, functions as a unique inhibitor of host acute inflammation and platelet aggregation. The inhibition mechanism of IRS-2 was described using the crystal structure (1.8 Å) of the protease-cleaved form of IRS-2. IrCD, a gut-associated cathepsin D protease, is critically involved in the initial step of blood protein digestion. Mechanisms of IrCD regulation were studied based on four crystal structures (1.5-2.3 Å) of the zymogen precursor, mature enzyme, and its complexes with active-site and exosite inhibitors.