With advancing age, the immune system undergoes changes that predispose to autoimmune reactivity. Aging reduces the efficiency of physical barriers, decreasing protection against invasive pathogens, and exposing previously hidden antigens in the body's own tissues. Self-antigens acquire alterations that increase their immunogenicity. In addition, the ability of innate immunity to eliminate infectious agents deteriorates, resulting in inappropriate persistence of immune stimulation and antigen levels exceeding the threshold for the activation of B or T cells. B cell turnover is reduced and numbers of naïve T cells decline to the advantage of increasing numbers of memory T cells. In parallel, the loss of co-stimulatory T cell molecules may increase reactivity of T cells, and render them less susceptible to downregulation. Since optimal immune reactivity requires a tight balance of transduction pathways in both T and B lymphocytes, and because these pathways are altered in systemic autoimmune diseases, we would like to propose that, with age, alterations of the immune receptor signaling machinery underlie the higher incidence of autoimmune phenomena in the elderly. Consistently, aging is associated with alterations in several components of the signaling complex in B cells, memory and naïve T cells, and a reduced activation of several lipid rafts-associated proteins. Because the coincidence of autoimmune disease with other ailments increases the burden of disease and limits therapeutic options in the aged, further investigation of these pathways in the elderly represents a challenge that will need to be addressed in order to devise effective preventive and therapeutic interventions.