Computer-assisted drug design is evolving as a source of innovation for drug discovery. In particular, de novo design approaches are being increasingly applied to find novel drug-like compounds, molecular scaffolds, and bioisosteric replacements for established or unwanted fragments. Although some of the early software tools had a certain tendency to generate compounds of limited chemical attraction, modern de novo design algorithms put a strong emphasis on the synthesizability and drug-likeness of machine-generated compounds. We give an overview of the various methodologies for virtual compound construction, evaluation, and optimization in machina, and how they can support medicinal chemistry projects in the early phase of drug discovery. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 742–759 DOI: 10.1002/wcms.49