This review covers the developments in the fields of de novo ligand design and scaffold hopping since 2006. De novo ligand design was introduced in 1991 as a purely structure-based method to suggest ligands for synthesis and was later augmented by ligand-based approaches. Both structure-based and ligand-based methods identify pharmacophores, as well as shape constraints, and subsequently match these with complementary features embedded into small-molecule topologies. Recently, significant attention has been paid to de novo ligand design in combination with biophysical fragment screening and X-ray structure elucidation. Scaffold hopping has evolved from a niche application of de novo design into a rapidly expanding suite of different software tools, which are used extensively in the pharmaceutical industry.