Human alpha-fetoprotein (hAFP) is a glycoprotein derived from the gut entoderm and expressed sequentially by cells of the yolk sac, fetal liver, and gastrointestinal tract. By adulthood, serum levels of alpha-fetoprotein (AFP) are undetectable in healthy, nonpregnant adults. Despite the clinical utilities of AFP monitoring in pregnancy and malignancy, much remains to be determined regarding its potential physiological functions. We focused on literature related to AFP's immunoregulatory role and its ability to modulate disease activity both in animal models of autoimmune disorders and in human clinical studies. Evidence suggests that AFP plays an important role in immunoregulation by inducing T-cell suppressor activity, downregulating dendritic-like cell antigen expression, and impairing the function of macrophages. Studies evaluating AFP and its effects in rodent models of autoimmune diseases have shown that AFP is associated with downregulation of inflammation. Observations in studies of pregnant patients with immune-mediated inflammatory diseases have also described potential correlations between AFP expression and disease activity during different stages of pregnancy and postpartum. We propose further prospective evaluations of AFP expression during pregnancy in inflammatory bowel disease patients to further correlate with disease activity and consider the potential of AFP as a novel therapeutic agent.