Computer-based analysis revealed that natural products exhibit a remarkable structural diversity of molecular frameworks and scaffolds that could be systematically exploited for combinatorial synthesis. Natural products offer a rich pool of unique molecular frameworks that complement “drug space”. They possess desirable druglike properties rendering them ideal starting points for molecular design considerations. This review provides an overview of chemotype diversity and molecular properties of collections of drugs and druglike molecules, pure natural products, and natural productderived compounds. Compared to druglike molecules, pure natural products contain more oxygen atoms and chiral centers, and have less aromatic atoms on average. Among the natural product library we identified more than one thousand scaffolds that were not contained in any other compound set analyzed. This outcome provides a basis for the design of new natural product-derived compound libraries. Our study demonstrates that computational chemical biology can assist in finding suitable molecular entities in collections of natural products for drug discovery.