endogenous ligand diversity, show weak or no NP enhancement. The increase in Clinical compound NP properties results from the use of just 176 NP fragments, which together make up, on average, 63% of the heavy atoms in post-2008 Clinical compound core scaffolds. Clinical pseudo-natural products (PNPs), where two or more NP fragments are combined in ways not achievable in Nature, have been rapidly increasing over time and comprise 67% of post-2010 Clinical compounds. The overall results are supportive of the occurrence of 'natural selection' being associated with many successful drug discovery campaigns. It has been proposed that NP-likeness assists drug distribution by membrane transporters and we further speculate that employing NP fragments may result in less attrition due to toxicity, a major cause of preclinical failure. There is huge untapped potential in further exploitation of currently used and unused NP fragments, especially in fragment combinations and design of PNPs, without the need to resort to chemically diverse ring systems and scaffolds. To exploit these opportunities, it is vital that 'NP awareness' is added to the repertoire of medicinal chemists. Sir James Black, discoverer of propranolol and cimetidine, famously stated that "the most fruitful basis for the discovery of a new drug is to start with an old drug." In the genomic era, the Black principle holds ever true, as medicinal chemists, knowingly or unknowingly, are repeatedly using a small group of established NP fragments to discover clinical candidates. We concur with the sentiment that "the local chemical space of a natural product can prove superior to the natural product itself." Adding NP fragment-based parameterisation to enhance machine learning models and influence generative chemistry is recommended.