Neural tube defects (NTDs) are serious congenital deformities of the nervous system that occur owing to the failure of normal neural tube closures. Genetic and non-genetic factors contribute to the etiology of neural tube defects in humans, indicating the role of gene-gene and gene-environment interaction in the occurrence and recurrence risk of neural tube defects. Several lines of genetic studies on humans and animals demonstrated the role of aberrant genes in the developmental risk of neural tube defects and also provided an understanding of the cellular and morphological programs that occur during embryonic development. Other studies observed the effects of folate and supplementation of folic acid on neural tube defects. Hence, here we review what is known to date regarding altered genes associated with specific signaling pathways resulting in NTDs, as well as highlight the role of various genetic, and non-genetic factors and their interactions that contribute to NTDs. Additionally, we also shine a light on the role of folate and cell adhesion molecules (CAMs) in neural tube defects.