Excerpt: In recent years, immunology has undergone an important change by admitting that immune components might operate as a network. Initially the concept was applied restrictedly to a web of variable regions (V-regions) in immunoglobulin molecules (Ig), and had little significance other than some form of regulation of immune responses. More recently, this view of the network has been fleshed out to include not only antibodies that link to other antibodies (i.e., anti-idiotypic antibodies), but also V-regions expressed on the surface of B and T lymphocytes at various development stages, as well as components of the somatic self (i.e., markers on cell surfaces and soluble macromolecules circulating in the body fluids). The initial ideas on immune networks (IN) were incomplete because they concentrated on the regulation of clonal immune responses, which are a manifestation of the system’s capacity to defend the body from infections, rather than on properties of the immune system (IS) that emerge from its network organization, such as natural tolerance and memory. We have called second generation immune networks this wave of research that includes theoretical advances, observations in unimmunized mice and humans, and novel therapeutics in autoimmune diseases, these generating a new burst of interest on IN. The main point of the present chapter is to consider the next step; one that follows naturally from assuming the second generation stance, i.e., that INs are a biological reality. In this perspective, the focus of interests change quite drasti­cally from the previous paradigm. Classically, immune responses represent the bulk of immunological lore. In the new perspective, immune responses are relegated to a peripheral role since infections are not always present and, when they are, the corresponding specific responses are mounted by an array of normally inactive, dis­connected B and T cells. These stand in high contrast to the naturally or internally activated, highly connected lymphocytes, the core of the IN. We speak, therefore, of a peripheral immune system, which is concerned with “conventional” immune responses to microbial antigens, accountable by the clonal selection theory. This contrast with the central immune system concerned with internally activated cells, tightly arranged in an interacting network.