Malocclusion is a deviation of a normal occlusal relationship, inflicting a notable aesthetic concern and functional hindrance on the affected individuals. Class III malocclusion is a type of malocclusion with several defined phenotypes, such as mandibular prognathism and macrognathia. The early concept of Class III malocclusion is thought to be governed heavily by genetic factors. However, major advancements in research discover that it is somewhat multifactorial, involving the interaction of both genetic and epigenetic factors at some levels. Modern genomic studies on the genetic mechanisms of facial variations show signs of future success in helping to understand the etiology of malocclusion and variation of dentofacial morphology. This knowledge gives helpful insights on the limits of what orthodontic treatments could achieve, which in turn influences orthodontist in diagnosing the severity of Class III malocclusion, choosing the appropriate treatment timing, planning the proper treatment plans, as well as preventing relapse from happening.