Antibodies with germline or close to germline configuration exist in vertebrates, and these so-called 'naturally occurring auto-antibodies' (NAb) are directed to self and altered self components. Such NAbs have been attracting increasing interest because several of them, including some in their recombinant forms, have therapeutic potential. Whereas a large number of IgM and IgG NAbs have tissue homeostatic roles, others modulate and regulate cellular and enzyme properties. This review describes some of these NAbs and emphasizes how these low-titer, low-affinity NAbs interact with self and altered self and show functional potency in homeostasis and regulation, in addition to in diseases such as infarction and systemic inflammatory response syndrome.