Illinois introduced mandatory newborn screening (NBS) for sickle cell disease (SCD) in 1989 and for cystic fibrosis (CF) in 2008. We examined maternal understanding of NBS for SCD and CF, and their knowledge of the genetics, symptoms, and treatments of both conditions. Our methods consisted of conducting interviews of inpatient post-partum women (>18 years and English speaking). Our results showed that of the 388 eligible participants, 34 self-identified as sickle cell carriers, 1 with SCD and 1 as a CF carrier. Almost 3/4 were African American (282/387). Although all but 5 women had prenatal care, only 35% (133/378) recalled their prenatal care provider mentioning NBS, and only 56% (217/388) of participants recalled nursery staff mentioning NBS. There was more self-reported familiarity with SCD (3.32/5) than CF (1.97/5, P < 0.001). Over 2/3 (260/388) of participants could not answer CF knowledge questions because they had never heard of CF. Among those who had heard of the conditions, mean knowledge scores were 66% for SCD (n = 372) and 63% for CF (n = 128). Bivariate analysis identified education, age, race, marital status, and insurance status as statistically significant. After linear regression education remained significant for both conditions. We conclude that in a sample of predominantly African American post-partum women, we found poor understanding of NBS, greater familiarity with SCD, and significant knowledge gaps for both SCD and CF. There are many missed educational opportunities for educating parents about NBS and specific conditions included in NBS panels in both the obstetric clinics and the nursery. © 2009 Wiley-Liss, Inc.