The focus of this chapter is on normal oro-facial embryogenesis; on the developmental basis for facial defects that fall within the holoprosencephaly spectrum; and on the genesis of common and unusual oro-facial clefts. A thorough understanding of normal morphogenesis coupled with appreciation of the dysmorphogenic events underlying the defects considered in this chapter should aid the reader in also better appreciating the developmental basis for many of the other abnormalities addressed in this text. The prenatal stages considered in detail are present from the 3rd through the 8th weeks of human gestation, with emphasis being placed on description of the development of the growth centers (prominences/processes) that comprise the human oro-facies. The presence and significance of some of these oro-facial growth centers for both normal and abnormal embryogenesis have been largely overlooked in the past, due in part to the paucity of early human embryos available for careful analyses with modern techniques. To aid in resolving this problem, descriptions provided herein are largely founded on a relatively recent series of scanning electron micrographs of human embryos. Regarding clefting, knowledge of normal oro-facial morphogenesis, coupled with basic research findings, support the premise that the junctions of the various growth centers correspond to the sites of common and unusual oro-facial clefts as described by Tessier in 1976 ; that the embryonic period is when the vast majority of oro-facial clefts are induced; and that, in most cases, the proximate cause of clefting is failure of the normal growth and development of single or adjacent orofacial growth centers. As for holoprosencephaly, both genetic abnormalities and environmental insults can underlie the dysmorphology.