More than two billion people will reach the age of 65 by 2050. Therefore, infectious disease/cancer-related morbidity and mortality of aged subjects is expected to rise. Several factors including impaired functions of body barriers and changes in microbial colonization contribute in increasing elderly susceptibility to infections and cancer. However, thymic involution, a hallmark of immunosenescence, is undoubtedly the principal component of this prominent problem. Although the thymus remains functional at older age, its pronounced diminished T-cell export rate is insufficient to sustain a competent naïve peripheral T-cell pool. Consequently, gradual dwindling in T-cell receptor (TCR) repertoire diversity takes place. As a result, the capacity of the elderly immune system to confer protection against cancer, acute/chronic infections or to respond to vaccination erodes. Therefore, there is an urgent need for the development of novel strategies aimed at: i) providing superior control of infectious diseases and cancer, and ii) improving responsiveness to all forms of immunotherapies.