Diseases started even before the existence of human beings. Therefore, when the civilization began, the biggest threats for human were diseases. Man has made several sincere attempts for the search of new drugs in order to cure and control different diseases. Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that accounts for about 85-95% of all diagnosed cases of diabetes. It is characterized by abnormalities in glucose homeostasis in many organs, and is associated with considerable morbidity and mortality. Extensive research has been carried out using rational drug design to identify and optimize new leads for molecular targets of T2DM, which include Heterocyclic compounds, metal complexes, H3 receptor antagonists, glucagon receptor antagonists and human incretin-degrading enzyme dipeptidyl peptidase IV inhibitors.