The concept of immunotherapy was in infancy when the first edition was written, and then major advances have been made not only with several major clinical trials, but also with the approval of Sipuleucel-T by the FDA for the treatment of cancer in 2010, resulting in a gradually narrowing gap between early scientific knowledge and the late development of immune-based therapies. Consequently, the significance and magnitude of these advances warrant a revision of this contribution--a revised edition that will provide a deeper understanding of the recent advances and discoveries of the function on the immune response and their applications in the development of novel therapies to treat human diseases. During the past five years, there have been significant advances in the understanding of the basic function of the immune response, and their relevant clinical applications. Some of the key discoveries include the identification of the new subset of helper T cells, new cytokines and their networks, and novel signal transduction mechanisms. For example, the identification of Th17 subset of helper T cells, in addition to Th1 and Th2 cells, not only advanced our understanding of the function of the basic immune response, but our awareness of the possible etiology and pathogenesis of diseases such as allergy, asthma, rheumatoid arthritis, and other auto-immune/immune system based diseases. The newly identified powerful cytokine networks, that regulate both innate and acquired immune responses, emerged as a result of the finding of the new cell types such as innate lymphoid cells and iNKT. Identification of the new cytokines and their networks have advanced our knowledge of the mechanisms involved in the maintenance of tissue homeostasis, including inflammation and tissue repair during stress and injury. For the clinical application’s perspective, there have been significant advances in oral immunotherapy for allergic disease, the treatment of HIV infection, the development of new monoclonal antibodies and their fragments to treat human diseases, and the immune cell based therapies for cancer. The development of HIV vaccines has seen dramatic changes over the last few years. There has been a shift from a sole focus on T cell vaccines to a holistic approach that pertains to the induction of both humoral and cellular elements. This entails induction of antibodies – both binding and neutralizing – to prevent infection. The cellular vaccination produces a safety net of CD8 T-cell responses to suppress the replication of the virus in the infected patients; and both of the effector arms are aided by helper T cells.