Context: Cleft lip and palate (CLP) is the most common congenital malformations in the face and neck. Given that the inheritance of this disease is multifactorial and both genetic and environmental factors play crucial roles in its creation, studying these factors may be a step toward reducing the prevalence of the disease in future generations. Method: For this study, we looked through several national and international databases, consisting of Scientific Information Database, IranDoc, ScienceDirect, Google Scholar, PubMed, and Scopus. Based on our search method, we found 800 published articles, of which 750 were obtained from the international databases, and the remaining 50 were extracted from the national databases. After data refining, 600 articles with eligible criteria remained for data extraction, and data related to embryological origin, classification and etiology, genes and environmental factors, and complications caused by CLP were collected. Results: The CLP etiology was multifactorial and involved both genetic and environmental risk factors. The primary purpose of this review was to give the reader an overview of studies on multifactorial causes of this congenital disability. The functions of genes are very different, indicating a high level of vulnerability in the cranial and facial growth pathways. Conclusions: These findings have advanced our understanding of genes associated with CLP and genetic polymorphisms involved in orofacial closure defects. The findings can create new clinical and molecular research opportunities.