The alpha 2 macroglobulins (A2M) are a family of abundant plasma proteins produced predominantly by the mammalian liver. Pregnancy zone proteins (PZP) of humans and rats are A2M family members that bind a wide variety of macromolecules including the important pregnancy-associated molecules such as vascular endothelial growth factor, placenta growth factor and glycodelin (also called PP14). Recently, a mouse gene analogous to PZP (A2M of pregnancy or A2Mp) was cloned. A2Mp has a unique pattern of expression in reproductive and cardiovascular tissues and, unexpectedly, is not expressed by liver. Since changes in heart function and remodeling of renal and uterine vasculature are amongst the earliest maternal responses to pregnancy, the product of the A2Mp gene has been postulated to systemically regulate these changes. A2Ms with and without non-covalently bound ligands also down regulate immune cell activation but promote immune cell migration, additional features associated with gestational success. Here, we review the A2M gene families of mice and humans, the predicted structural relationships between A2M and its pregnancy induced forms and the postulated roles for this gene family in normal pregnancy.