AbstractThis chapter focuses on computational techniques for identifying and optimizing lead molecules, with a special emphasis on natural compounds. A number of case studies have been specifically discussed, such as the case of the naphthyridine scaffold, discovered through a structure-based virtual screening (SBVS) and proposed as the starting point for further lead optimization process, to enhance its telomeric RNA selectivity. Another example is the case of Liphagal, a tetracyclic meroterpenoid extracted fromAka coralliphaga, known as PI3Kα inhibitor, provide an evidence for the design of new active congeners against PI3Kα using molecular dynamics (MD) simulations. These are only two of the numerous examples of the computational techniques’ powerful in drug design and drug discovery fields. Finally, the design of drugs that can simultaneously interact with multiple targets as a promising approach for treating complicated diseases has been reported. An example of polypharmacological agents are the compounds extracted from mushrooms identified by means of molecular docking experiments. This chapter may be a useful manual of molecular modeling techniques used in the lead-optimization and lead identification processes.