Natural autoantibodies (autoNAb) recognize self antigens and are an important component of the immune system, as species ranging from invertebrates to vertebrates have polyreactive IgM NAbs. In higher vertebrates, different polyreactive autoNAbs isotypes are also frequently encountered and autopolyreactive IgG NAbs are largely predominant compared to low-titer monoreactive IgG NAbs specific for either self or non-self antigens. Autopolyreactive NAbs manifest the capacity to recognize three-dimensional structures and thus represent a fundamental feature of the immune system that has long been preserved during evolution. NAbs are produced in a continuum of functional and phenotypic tiers of B cells and are likely to derive from proteins initially selected to build the organism that were adapted through evolution to recognize environmental constituents, while preserving their capacity to recognize self antigens. The clonal selection is considered the predominant mechanism of the regulation of the immune system complexity but growing evidence suggests that autoNAbs are also actively implicated. In all species NAbs reacting with either self or non-self antigens constitute a vast network of infinite interactions providing high complexity, stability and plasticity. This evolutionary process was intended to allow the effective recognition of environmental antigens, immune memory, immunoregulatory phenomena, as well as tissue homeostasis. The present article is intended to illustrate the history and the current and future developments in our understanding of self and non-self recognizing NAbs to ultimately enlighten the complexity of the immune system regulation.