Aging is a post-maturational process, biologically characterized by the progressive failure to maintain or restore the physiologic homeostasis. Such a complex phenomenon is influenced by the interaction among genetic, epigenetic, environmental, behavioral and socio-economic factors and involves the whole body, including immune system. The age-related immune system changes, collectively termed immunosenescence and historically defined as a state of immunodeficiency, actually represent a complex remodeling that entails the increase of some immune functions and the decrease or invariability of others. These adjustments may either successfully result in a longstanding active immune system with a greater chance of long survival, or unsuccessfully lead to a dysregulated immunity with a higher risk of infections, malignancies and autoimmune diseases. Revealing the complete scenario of the biological events occurring in the immune system with advancing age might allow to identify immunosupportive treatments and/or behaviors direct to positively modulate the immunosenescence process.