Drug delivery systems, vaccination, and diagnostic imaging are the main aspects that enhance the effectiveness of human health and safety. This system protects an organism against microbes, viruses, parasites, and allergens. The immune system represents the level of the ontogenic and phylogenetic development of a biosystem. The degree of efficiency to protect against infection varies in different organisms. Overall, the functional mechanism of the immune system is complicated. Any molecule, or a pathogen entering the human body or a biosystem, has to face various components of the immune system. It is imperative to understand the concept of the interactions between nanomaterials and the components of the immune system. This understanding will improve, improvise, and elevate the degree of clinical translation of nanomedicine in the field of human health and safety. There seems to be an enormous scope of studies related to the intricacies of interaction occurring at the bio-nano-interface. These efforts will guide to design the rational nanomaterials that are either fabricated or synthesized with specific targets. The study of the modes or the patterns involved during the interactions between nanomaterials and the immune system can maintain the appropriate defense system of the individual against infections, xenobiotics, and any foreign molecule. This chapter deals with the applications of nanomaterials in the delivery system, competence of nanomaterials concerning the immune system, immunomodulation, immunosuppression, immunostimulation, and interactions between various nanomaterials and the components of the immune system.