Senchina and Kohut current immunization strategies are not sufﬁcient in them- selves to combat increased infectious disease rates in the elderly (McElhaney 2005). In addition to higher rates of infectious disease, older adults experience increased incidences of other medical conditions as well. Rates of autoimmune disease and related inﬂammatory conditions are greater in geriatric populations as compared with other segments (Franceschi et al 2000b; Wick et al 2000; Hasler and Zouali 2005). Immunosenes- cence may also render older individuals more susceptible to cancer (Ben-Yehuda and Weksler 1992; Sarkar and Fisher 2006). The increased rates of infectious disease, autoimmune disorders, inappropriate inﬂammatory conditions, and cancer among older adults all translate to increased rates of clini- cal visits, home care nursing, and hospitalization (Nichol 2005; O’Meara et al 2005). Thus, the need to identify and implement strategies to counteract immunosenescence is a pressing issue, with physicians and researchers actively investigating possible compensatory therapies. Physical ex- ercise has been proposed as one such therapy. Existing data suggest that moderate exercise may counteract the effects of immunosenescence through several diverse mechanisms (Bruunsgaard and Pedersen 2000; Drela et al 2004; Kohut and Senchina 2004). Exercise is also an appealing therapy from a logistical vantage point, as it is relatively easy to implement, requires little cost or equipment, and can be performed in either clinical or home settings. In this review, we will explore the current knowledge regarding exercise and immunosenescence, how the imple- mentation of an appropriate physical activity program in older populations may lead to beneﬁcial clinical outcomes, and how inappropriate exercise may detrimentally impact health. Compared with previous reviews, the present work focuses on application of current data to the clinical setting and also provides an updated review of the literature. Immunosenescence Immunity is classically conceptualized as two distinct but interacting systems: innate and adaptive. Innate immunity may be thought of as the basal or ﬁrst immune response. Upon infection, innate resistance mechanisms (including both cellular and chemical systems) are quickly and automatically activated to respond to the invader. Innate immunity may or may not be adequate for a given threat. If innate immunity is not adequate and a more specialized defense is required, adaptive immunity is launched. Adaptive immunity utilizes innate immunity in its attack, but also develops additional responses specific to the particular threat. There are several important differences between innate and adaptive immunity. While innate immunity may act within seconds of detecting a threat, the construction of a specialized adaptive immune response generally requires 2–5 days. Repeated exposure to a given pathogen will enhance the adaptive immune response, but not the innate, because only adaptive immunity has immunological memory (dis- cussed below). Immunosenescence affects both innate and adaptive immunity. In order to understand the clinical consequences of immunosenescence, it is beneﬁcial to ﬁrst brieﬂy explore the biological changes it induces at both the cellular and molecular levels. A more detailed review of this topic has been presented elsewhere (Miller 1996; Pawelec et al 1999; Effros 2001; Kohut and Senchina 2004). Immunosenescence and adaptive immunity The bulk of research on immunosenescence has focused on changes to the adaptive immune system. Adaptive immunity includes antigen-speciﬁc cells such as B cells and T cells, the cytokines they secrete, and cytolytic mediators, but also recruits components of innate immunity in its efforts. Most research has focused on the T cell, which can be divided into two broad classes based on cell surface expres- sion of either CD4 or CD8. T cells expressing CD4 are also known as “helper T cells.” Once engaged by antigen, they are able to stimulate other cells towards effector states. In general, Th1 CD4 T cells prime CD8 T cells and B cells, whereas Th2 CD4 T cells prime B cells and macrophages. T cells expressing CD8 are termed “cytotoxic T cells.” CD8 T cells destroy other infected cells by a directed release of cytotoxic molecules. Before encountering antigen, T cells are said to be naïve; upon antigen encounter, they become effector cells. Following antigen clearance, most effector cells undergo apoptosis (cell suicide), but a few remain as “memory” cells committed to that particular antigen and capable of responding more rapidly to the same threat in the future. The generation of memory cells is one of the under- lying principles of vaccination. Thus, both CD4 and CD8 T cells are necessary for attacking and clearing infectious agents, and thwarting repeated infections. Aging is associated with declines in overall T cell number and function, and shifts in subpopulation composition (Schwab 4 Clinical Interventions in Aging 2007:2(1)