The presence of natural auto-antibodies (NAbs) in normal range/activity in healthy individuals is essential for body to maintain hemostasis, which are directed to self and altered self-components, while abnormal activity of this system can be associated with several health related diseases. It has been shown that NAbs regulate immune system, and can be changed during the individual's life. In other word, the level and pattern of Nabs is among the main factors to define the state of the body, suggesting their prognostic values as markers of immune system impairment such as autoimmunity and cancer. Such NAbs have gained substantial attention because several of them, including their recombinant forms, have therapeutic potential (e.g., programmed cell death-1 [PD-1, Pdcd1], which some of its inhibitors have been approved by FDA for cancer therapy). Whereas a large number of IgM and IgG NAbs have a key role in tissue homeostasis, while others modulate cellular and enzyme properties. The aim of current review is to give an overview about some of these NAbs and how these low-titer/affinity interact with Ag in homeostasis, with particular emphasis on related diseases such as systemic inflammatory response syndrome and cancer, and their application as potential therapeutic target for cancer therapy.