Maternal serum AFP screening has had significant clinical impact on reducing unrecognized anencephaly and open neural tube defects at delivery. In addition, a growing number of other associations with maternal serum AFP elevations have become apparent since antepartum screening has become commonplace. We present in this review a clinically oriented approach to understanding the physiologic basis of maternal serum AFP elevations, both true- and false-positives. Compartmentalization of etiology, fetal and maternal, and routes of communication, amniotic fluid and placenta, allows a more logical approach to developing a differential diagnosis in this group of patients. In evaluating an elevation in maternal serum AFP, it is first necessary to consider the amount of fetal production by confirming the gestational age of the fetus and the number of fetuses present. Adjustments for maternal factors (weight, race, diabetes) must also be made. Fetal developmental defects which may lead primarily to leakage of the fetal proteins into the surrounding amniotic fluid with secondary elevations of maternal serum AFP enter into the differential diagnosis. The placenta itself is probably not a production source of AFP, but when the placenta is abnormal, a greater amount of AFP may be transported to the maternal circulation. Although our thoughts frequently do turn first to an increased maternal serum AFP reflecting an increased AFP concentration in the amniotic cavity with greater transference "across the membranes," in fact a far more common etiology is an increased transfer from the fetal circulation to the maternal via the fetal-maternal interface within the placenta. This is supported by the simple fact that the vast majority of maternal serum AFP elevations are not associated with amniotic fluid AFP elevations; the amniotic fluid AFP concentrations are usually normal. Thus, in circumstances where the fetal anatomy is grossly normal and there is not another explanation for elevations in maternal serum AFP, the placenta, either secondary to providing increased areas of transport or in providing an abnormal endothelial barrier, allows for greater transfer of fetal serum, and thus AFP, into the maternal compartment. An abnormal placenta is also a likely explanation for the increased risk of adverse pregnancy outcome that is associated with increased maternal serum AFP elevations for which no obvious etiology is found. The case herein reported suggests that an abnormal placenta which provides an altered interface for AFP flow between the fetal and maternal circulations may in fact be the etiology of the significant elevations of maternal serum AFP seen in cases of triploidy.(ABSTRACT TRUNCATED AT 400 WORDS)