Amelogenesis is the biological process that produces tooth enamel, the hardest tissue in the body. When successful it results in a biocomposite with ~96 wt.% hydroxyapatite mineral nanocrystals surrounded by ~1 wt.% organic protein and ~3 wt.% water. Enamel is surprisingly resistant to fatigue and fracture due to its complex hierarchical microstructure and unique decussating patterns of the enamel rods. Genetic defects can interrupt enamel formation, resulting in excessive organic content, premature termination of amelogenesis, or production of aprismatic enamel, depending on the affected gene(s). Collectively, these mutations are described as the genetic disease Amelogenesis Imperfecta (AI), which causes stained, sensitive, and mechanically weak teeth. Here, a materials science description of the mechanical and compositional characteristics of AI-afflicted enamel is compared to other enamel systems, including healthy human enamel and the primitive, aprismatic enamel of crocodilians. A better understanding of AI enamel could lead to therapeutic options for patients.