Modern medicine and advanced combinatorial chemistry owe much of its progress towards the development of small molecules as the therapeutic approach for disease treatments. Small molecules have been evolved as a potential tool for development of novel and effective therapeutics for the past several decades. Typically molecular weight less than 1000 Dalton make small molecules to be easily dissolute and absorbed in gastrointestinal tract following the oral administration of the drug. Their smaller size also enabled them to be manufactured in small capsule and pills. Most of the orally active compounds that have achieved Phase II status follow the Lipinski's rule of Five i.e., molecular weight ≤ 500 Dalton; log P ≤ 5; H-bond donors ≤ 5; H-bond acceptors ≤ 10. Exceptions to the rule of five mostly occur among the compound of natural origins like flavonoids, alkaloids, and antibiotics. Very often, a small molecule having the number of rotatable bonds more than ten are suspected for the poor bio-availability. Small molecules with the polar surface area of ≤ 60 – 70 are reported to act within the central nervous system quite efficiently. Additionally, if the sum of the nitrogen and oxygen atoms are ≤ 5, there is a high probability that the small molecule will cross the blood-brain barrier. Small molecules that penetrate the blood-brain barrier represented a leap forward in therapeutic developments for the psychological and neurological disease. Additionally, drugs that discriminately act at neuronal versus peripheral sites typically produce fewer treatment-related adverse effects.