The term drug design describes the search of novel compounds with biological activity, on a systematic basis. In its most common form, it involves modification of a known active scaffold or linking known active scaffolds, although de novo drug design (i.e., from scratch) is also possible. Though highly interrelated, identification of active scaffolds should be conceptually separated from drug design. Traditionally, the drug design process has focused on the molecular determinants of the interactions between the drug and its known or intended molecular target. Nevertheless, current drug design also takes into consideration other relevant processes than influence drug efficacy and safety (e.g., bioavailability, metabolic stability, interaction with antitargets).This chapter provides an overview on possible approaches to identify active scaffolds (including in silico approximations to approach that task) and computational methods to guide the subsequent optimization process. It also discusses in which situations each of the overviewed techniques is more appropriate.