To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy.We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy.Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist.Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy.