Rational drug design approaches represent an important alternative strategy to the discovery of new therapeutics based on simply serendipity. Computational chemists have to understand the peculiar aspects linked to the biological system in study and on this basis choose the right collection of complementary in silico approaches to tackle in the better way the medicinal chemistry problem in study. In this chapter several examples of successful applications of in silico approaches for lead/drug discovery are presented. In the first paragraph are discussed interesting structure based methods to design inhibitors of protein kinases, while in the second both structure and ligand based techniques are exploited in a consensus fashion to develop novel Adenosine A3 receptor antagonists. The last paragraph presents an overview of ligand based virtual screening and an example of a successful application of this approach to identify a small molecule agonist of the NTS1 receptor. Even if the cases reported cannot cover completely the complexity of the computational techniques available nowadays, they embody different interesting examples useful to understand the potentialities, limits and pitfalls of modern molecular modeling approaches.