Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes.  Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand.  The multi-target drugs which impact multiple targets   simultaneously are better at controlling complex disease systems and are less prone to drug resistance.  Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and   introduce the approaches of designing multiple ligands and the procedure of optimization particularly.  A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile.  On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.