The severity of hemolytic disease of the fetus or newborn can be assessed with certainty only by measurement of fetal parameters. However, these invasive procedures are not without risk for the fetus. Most erythrocyte antibodies do not cause significant hemolytic disease of the fetus or newborn and various assays are available to assist obstetricians in predicting the likely effect of maternal alloantibodies on fetal erythrocytes. Initially, immunohematologic tests are performed on maternal serum to identify antibodies with a potential for causing hemolytic disease of the fetus or newborn. Antibody concentration is measured by indirect antiglobulin technique titration, or where possible (for anti-D or -c), by quantitation. When used consecutively throughout pregnancy, these tests will reveal a trend that helps to predict the likelihood of hemolytic disease of the fetus or newborn. Functional assays (antibody-dependent cell-mediated cytotoxicity and chemiluminescence) are probably superior to serologic tests for predicting hemolytic disease of the fetus or newborn. Unfortunately, the assays do not reflect accurately the in vivo conditions for a given patient. Knowledge of the immunoglobulin subclass can help to assess the hemolytic potential of maternal antibody, but quantitative measurement of subclasses is still experimental. Diagnostic testing should be approached in a structured manner, commencing with simple serology, followed, in selected cases, by more complex functional assays and indirect fetal tests to identify those fetuses at greatest risk. This approach will enable direct fetal tests to be undertaken only when there is strong suspicion of severe hemolytic disease of the fetus or newborn.