The development of dental enamel can be adversely affected by environmental factors and by alterations in the genes important to normal enamel formation or metabolic changes encountered in some inherited conditions. In addition, the etiology of some enamel defects, such as molar-incisor hypomineralization (MIH), is likely to involve both environmental and hereditary factors. Genetic mutations in the proteins involved in enamel formation may result in a group of conditions known as amelogenesis imperfecta (AI). AI may present clinically as hypoplastic defects, which may be expressed as thin or missing enamel, as pits and grooves, or as hypomineralized enamel (classified as hypocalcified or hypomature enamel) which is discolored and weakened due to the reduced mineral content. Although the traditional diagnosis of AI is based mainly on the clinical appearance of the defects, the genotypes of many AI phenotypes have now been identified. The hypoplastic autosomal dominant AI mutations are typically associated with changes in ENAM or AMELX genes, which encode for proteins essential for the extracellular matrix formation that helps guide and develop the unique enamel structure and shape. In contrast, the hypomineralized autosomal recessive and dominant AI phenotypes are associated with mutations in the genes coding for enzymes kallikrein-4 (KLK4) and metalloproteinase (MMP20), as well as the proteins FAM83H and WDR72. In addition to the 20 or so AI conditions with known genetic mutations and phenotypes, there are about 80 hereditary syndromes that can have enamel defects, with hypoplastic enamel being the most common phenotype. The common clinical problems associated with enamel defects are poor esthetics, tooth sensitivity, and increased risk for caries, cusp fracture, tooth wear, and erosion. The management of patients with enamel defects should be focused on early diagnosis, improvement of esthetics, and restoration and preservation of the dentition and often requires interdisciplinary teams consisting of general dentists, pediatric dentists, orthodontists, and prosthodontists. Despite major advances in the understanding of the etiology of defects of enamel formation, further research is required to help identify the as-of-yet-unknown etiologies and to deepen our understanding of the genetic and environmental factors contributing to the pathophysiology of developmental enamel defects.