Ticks are of vast medical and veterinary public health importance due to direct damage in livestock by its hematophagous feeding habits and its potential as a vector capable to transmit infectious agents such as Tick-borne diseases. Currently, the knowledge of vertebrates’ immune system contributes to the advance in vaccine and drug development, resulting in new drugs that help to control human and livestock pathogens. Unfortunately, very small advances have been achieved in tick’s immune system that could help to develop new strategies designated to control tick-borne diseases and other arthropod vectors. On this subject, the study of the mechanisms involved is transcendental as is also the study on molecules, cells, and regulation of immune response involved in signaling pathways in ticks. The progress on the understanding of ticks’ physiology represents a necessary advance in molecular approaches related with a tick’s immune response, involved in host-vector-pathogen interaction, and, in turn, evolutionary relationships. Current knowledge on tick’s immune response to different kinds of pathogens is described in this chapter and the use of modern molecular tools to fill the gaps on different aspects in tick immunobiology that still is unclear or under study.