Cleft lip and palate (CLP) are common birth defects with complex etiology, often occurring as part of chromosomal, Mendelian, or teratogenic syndromes. While significant progress has been made in identifying genetic and environmental triggers for syndromic CLP, the etiology of non-syndromic (isolated) forms remains poorly understood. Recent studies using epidemiology, careful phenotyping, genome-wide association studies, and animal models have identified several distinct genetic and environmental risk factors for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translation research. The review focuses on non-syndromic CLP, discussing epidemiologic clues, environmental contributions, genetic architecture, and phenotyping. It also explores gene discovery, molecular pathogenesis, and clinical implications, including long-term outcomes and the potential for improved prevention and treatment.Cleft lip and palate (CLP) are common birth defects with complex etiology, often occurring as part of chromosomal, Mendelian, or teratogenic syndromes. While significant progress has been made in identifying genetic and environmental triggers for syndromic CLP, the etiology of non-syndromic (isolated) forms remains poorly understood. Recent studies using epidemiology, careful phenotyping, genome-wide association studies, and animal models have identified several distinct genetic and environmental risk factors for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translation research. The review focuses on non-syndromic CLP, discussing epidemiologic clues, environmental contributions, genetic architecture, and phenotyping. It also explores gene discovery, molecular pathogenesis, and clinical implications, including long-term outcomes and the potential for improved prevention and treatment.