Lyme disease, also known as Lyme borreliosis, a common vector-transmitted illness across the Unites States and Europe, is caused by the pathogen Borrelia burgdorferi, which is transmitted by Ixodes scapularis ticks. While ticks are known to transmit a diverse set of bacterial, protozoan and viral disease agents, there are only limited investigations addressing how Ixodes immune responses influence the survival or persistence of specific pathogens within the tick. In North America, I. scapularis transmits a wide array of human and animal pathogens including a group of pathogenic bacteria, known as Borrelia burgdorferi sensu lato complex. Due to the evolutionary divergence from other bacteria, and the possession of a unique cellular structure, B. burgdorferi cannot be classified as a conventional Gram-positive or Gram-negative bacteria, instead they are classified as a spirochete. Additionally, key pattern recognition molecules or PAMPs, such as lipopolysaccharides and peptidoglycans, are absent or structurally distinct in B. burgdorferi. Thus, the wealth of knowledge generated in other model arthropods, regarding the genesis of host immune responses against classical bacterial pathogens, might not be applicable to B. burgdorferi. The primary goal for this dissertation is to characterize components of the tick immune responses that modulate B. burgdorferi infection and use this information to better understand specific aspects of tick immunity as well as to contribute to the development of new strategies that interfere with pathogen persistence and transmission. The following aims were addressed: assessment of the expression profile of the I. scapularis innate immune transcriptome to identify genes that are induced in the B. burgdorferi-infected vector. Next, a select set of pathogen-inducible gene-products was further studied for their possible harmful or beneficial roles in pathogen persistence in the vector. Based on recent findings in other disease vectors as well data generated within this thesis, I particularly focused on characterization of two select sets of B. burgdorferi-inducible tick gene-products that are potentially involved in maintenance of gut microbe homeostasis (Dual oxidase and peroxidase) and events linked to phagocytosis (Rho GTPase).