Non-syndromic tooth agenesis represents a common odontogenic condition that should be managed by a multi-disciplinary specialty team. The genetic basis for agenesis of teeth reflects the key transcriptional events involved in mesenchymal-epithelial interactions during tooth formation. Mutations of genes, including WNT10A, PAX9, MSX1, AXIN2, and EDA, are implicated. Clinicians should be aware of familial history of tooth agenesis. Tooth agenesis impacts alveolar/craniofacial growth and the treatment may involve pediatric dentists, orthodontists and prosthodontists early in the management of these individuals. In all cases, the establishment of oral health, stable occlusion and development of a conceptual framework for treatment resulting in efficient tooth replacement and esthetic outcomes should be considered in the mixed dentition phase. Definitive tooth replacement using conventional or implant prostheses should be reserved for individuals with complete facial growth and maturation.