An Ab molecule or a BCR that is able to bind multiple structurally unrelated Ags is defined as polyreactive. Polyreactive Abs and BCRs constitute an important part of immune repertoires under physiological conditions and may play essential roles in immune defense and in the maintenance of immune homeostasis. In this review, we integrate and discuss different findings that reveal the indispensable role of Ag-binding polyreactivity in the immune system. First, we describe the functional and molecular characteristics of polyreactive Abs. The following part of the review concentrates on the biological roles attributed to polyreactive Abs and to polyreactive BCRs. Finally, we discuss recent studies that link Ig polyreactivity with distinct pathological conditions.