A substantial proportion of circulating antibodies in healthy individuals exhibit self-reactivity. These antibodies, referred to as natural autoantibodies, are thought to arise naturally without actual antigen stimulation as they are present in human cord blood and in mice housed in germfree conditions and fed an antigen-free diet. Natural autoantibodies are mainly of the IgM class, unmutated, and typically polyreactive. They provide critical early protection against pathogens, and play important roles in maintenance of homeostasis and modulation of innate and adaptive immune responses, thereby conferring protection from rampant autoimmune and inflammatory injuries. In this review, we summarize current information regarding the properties of natural autoantibodies and the B cells that produce them, their roles in immunity and autoimmunity, their mechanisms of action, and their therapeutic potential.