Thiophene nucleus has been established as the potential entity in the largely growing chemical world of heterocyclic compounds processing promising pharmacological characteristics.The knowledge of various synthetic pathway and the diverse physicochemical parameters of such compounds draw the especial attention of medical chemist to produce combanitorial library and carry out exhaustive efforts in the search of lead molecules. Thiophene is a five membered , sulfur containing hetero aromatic ring generally used as building block in drugs. It is structural metabolism leads to the formation of reactive metabolites. This compounds are widely spread in nature & have diversified application in design of new drug molecule. Thiophene has been established as the potential entity in largely growing chemical world of heterocyclic compounds possessing a pharmacological characteristics. A series of thiophene compound can be synthesize through various routes with pharmacological activity. The simple five – membered heterocycle are thiophene, with sulphur atom. It also undergo electrophilic aromatic substitution very readily.Sulphur is the least electron donor as compare to nitrogen and oxygen.Thiophene is similar to benzene in reactivity. Thiophene is the least reactive of the three because the p orbital of the lone pair of electrons on sulphur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with 2p orbitals on carbon is less good. Thiophene undergo more or less normal Friedel- Craft reactions, although the less reactive unhydrides( aceticunhydride, Ac2O ) are used instead of acid chlorides, and weaker Lewis acid than AlCl3 are preferred. The regioselectivity is the – the 2- position is more reactive than 3- position. The present review includes the properties, synthesis, and a wide spectrum of biological activities of thiophene based scaffolds, and summary of thiophene containing active pharmaceutical ingredients (APIs) available in the market.