The structural evolution and thermodynamic stability of a series of small neutral gold clusters containing two to twenty atoms are reviewed including the most recent assignment of some lowest-lying isomers. It is followed by a thorough report on their interaction and binding mechanism with some popular anticancer drug molecules, i.e. mercaptopurine, pramipexole and 5-fluorouracil. All relevant calculations are performed using density functional theory with different functionals and basis sets. In gas phase and neutral conditions, interaction of these molecules with a gold surface, modeled by a small cluster, is mostly dominated by the Au  X (X ¼ S, O) covalent bond and partially stabilized by the AuH  N hydrogen bond. In addition, the Surface-enhanced Raman scattering (SERS) mechanism is also analyzed in detail. The N  H, CQO and CQS bending and stretching vibrations are found as major contribution to the SERS phenomenon of the drug on gold surface in neutral solution; the most strongly enhanced band in an acidic environment is mostly due to the AuH  S coupling. Mechanisms of the drug release are examined under some specific conditions such as the effect of protonation and presence of cysteine (an amino acid) in the intracellular body matrix.