Natural autoantibodies (NAbs) are a seminal part of the immune system originating from B1-cells and are mainly of the IgM isotype having generally low-binding affinity. NAbs fulfill important and diverse immunological roles, providing very early innate immune protection, ensuring removal of possible autoantigens by scavenging dead or apoptotic cellular debris and possibly also improving cardiovascular profile. The generation of NAbs is not dependent on exogenous antigen stimuli but seems to be a profound element of the immune system as it evolves and develops. In parallel with the "Burnetian" negative selection, there is a constant autoantigen receptor-mediated signaling critical for the survival of certain lymphocytic clones, a phenomenon termed "positive selection". A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen was shown to promote B-cell accumulation and serum autoantibody secretion. Thus, these B cells that were subject to positive selection generated and maintained the autoreactivity of this model. With the understanding of the physiology of NAbs, their involvement in additional immune functions is found. These understandings direct us as to how to harness NAbs as a future therapy for autoimmune disorders.