Neural tube closure (neurulation) is a complex process involving many cell phenomena. Both extrinsic and intrinsic forces are essential to elevate the neural plate into the neural folds and to bring the folds into apposition for closure. Extrinsic forces involve the underlying mesenchyme cells and extracellular matrix, nonneural ectoderm, the gut tube and notochord, and cell surface glycoproteins. Intrinsic forces involve cytoskeletal elements and microtubles, region-specific variations in cell cycle times, positioning of daughter cells during cell division, and rearrangement of neuroepithelial cells. Closure itself begins in the cervical region and proceeds in rostral and caudal directions. In the mouse, multiple additional closure sites occur in the cranial region, but in humans there appears to be only one additional site, at the rostralmost tip of the forebrain. Differences in closure exist in cranial vs. caudal regions, and these variations may play a role in the types of neural tube defects that occur. In this regard, virtually all of the cell phenomena involved in closure present targets for insults leading to abnormalities, although specific mechanisms responsible for neural tube defects have not been well-defined. It is also not clear what the role of folic acid is in normal neural tube closure, although the vitamin may be important for DNA synthesis and/or methylation of macromolecules, such as DNA and protein. Until more is learned about the regulation of neural tube closure at the genetic and cellular levels, understanding how defects occur and developing methods for their prevention will be limited.