Aging is associated with defects in the cells of the innate immune system, in both their function and number. During the last decade, new evidence has revealed impairment in the early stages of the activation processes that trigger innate immune cells. In this review, the impact of aging on signal transduction in macrophages (MΦs), as pivotal representatives of innate immunity, is presented. Emphasis is put on the classical intracellular pathways of MΦ activation in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). The critical analysis of the literature reveals that, when intracellular signaling defects occur, the ability of MΦ s to respond appropriately is significantly compromised. Taken together, these observations may help explain why aged individuals have inflammatory and immune defects that range from decreased capacity to fight infections to delayed healing of dermal wounds. Gaining an understanding of the nature of the defects in innate immune cells, such as MΦ s, may shed light on the development of therapeutic strategies aimed at restoring innate immune function in aged individuals so they can better combat infectious challenges.