50 years ago, people with sickle cell disease (SCD) were discouraged from becoming pregnant, but now most should be supported if they choose to pursue a pregnancy. They and their providers, however, should be aware of the physiological changes of pregnancy that aggravate SCD and pregnancy's unique maternal and fetal challenges. Any maternal endothelial damage from a poorly perfused placenta has the potential for being superimposed on the endothelial damage of SCD. The immunological and mechanical changes of pregnancy contribute to an increased susceptibility to certain infections. Activation of the complement system and increased neutrophils may contribute to the increase in vaso-occlusive crises during pregnancy. There is an increased demand for red cell mass that is often not achievable without transfusion. Cardiac output increases by 45%. The anatomic and physiologic changes of pregnancy increase the risk of kidney injury. Pregnancy is a hypercoagulable state which confers an increased risk of thrombosis. Maternal problems can arise from chronic underlying organ dysfunction such as renal disease or pulmonary hypertension, from acute complications of SCD such as acute anemia, vaso-occlusive crises and acute chest syndrome, and/or from pregnancy-related complications such as preeclampsia, sepsis, severe anemia, thromboembolism and need for cesarean delivery. Fetal problems include alloimmunization, opioid exposure, fetal growth restriction, preterm delivery, and stillbirth. Prior to and during pregnancy, in addition to the assessment and care that every pregnant patient should receive, patients with SCD should be evaluated and treated by a multidisciplinary team with respect to their unique maternal and fetal issues.