Non-invasive prenatal testing (NIPT) is performed worldwide to detect common chromosomal aneuploidies. The analysis of cell-free DNA (cfDNA) in maternal blood for NIPT is highly accurate for the detection of the main fetal trisomies: 21,18, and 13. However, false-positive, false-negative, and non-reportable results can occur, and these can have biological causes. Understanding the causes of unexpected NIPT results is essential to enable clinicians and genetic counselors to counsel patients comprehensively and appropriately, both prior to testing as well as after receiving the test results. The classification of non-reportable results from cfDNA analysis is important in order to provide women with precise information. In addition to technical issues, there are biological reasons for discordant results, which can be either fetal or maternal in origin. Contributing fetal factors include insufficient or absent fetal fraction, fetoplacental mosaicism, and the presence of a vanishing twin. In some pregnant women that test positive for NIPT, multiple chromosome aneuploidy has been reported as a result of suspected malignancy, and cancer has been found. False-positive and false-negative results may be the result of placental biology and not a failure in the actual test platform. Explaining the placental origin of cfDNA provides the patient with a clear view of the abilities and limitations of cfDNA-based prenatal screening.