We report seven infants of diabetic mothers, affected with holoprosencephaly malformation sequence. An additional 15 cases assembled from personal communications and the literature indicate that holoprosencephaly, like neural tube, cardiac, and caudal defects, is specifically increased in children of diabetic mothers. Incidence figures from newborn surveys demonstrate a risk for holoprosencephaly in infants of diabetic mothers comparable to the 1% risk for caudal regression malformation sequence. The embryologic timing of cranial, cardiac, and caudal defects emphasizes the need for pregnancy planning and diabetes control.