Orthodontics, the oldest discipline of dental specialty concerns with the treatment of malocclusion both dental and skeletal. Although etiology of malocclusion is multifactorial, genes do have influence on this condition, beside their role in mechanism of tooth movement and unwanted sequel like external root resorption following orthodontic treatment. This short communication will focus the issue on role of gene in various conditions which have paramount effect either on the etiology of malocclusion or mechanism by which tooth movement occurs. Human genome project and future advancement in genomic medicine will help us in clear identification of conditions causing mutation and the unsolved zigzag puzzle of molecular interaction can be solved.