The general goal of drug discovery is to identify novel compounds that are active against a preselected biological target with acceptable pharmacological properties defined by marketed drugs. Scaffold hopping has been widely applied by medicinal chemists to discover equipotent compounds with novel backbones that have improved properties. In this article we classify scaffold hopping into four major categories, namely heterocycle replacements, ring opening or closure, peptidomimetics and topology-based hopping. We review the structural diversity of original and final scaffolds with respect to each category. We discuss the advantages and limitations of small, medium and large-step scaffold hopping. Finally, we summarize software that is frequently used to facilitate different kinds of scaffold-hopping methods.