We have used three measures of natural product (NP) character to assess compounds reaching the Clinic (phases 1-4), as well as Reference compounds acting at the same biological targets. While calculated NP-likeness is in overall decline in drug discovery and in Clinical compounds, the results show that the 'NP signal' remains strong because of widespread exploitation of a relatively small pool of NP fragments. Notably, pseudo-natural products (PNPs), which contain NP fragments but are inaccessible by Nature's known biosynthetic pathways, have been increasing progressively over time and make up 67% of Clinical compounds first disclosed since 2010. Inevitably the growth of PNPs in Clinical molecules cannot continue at the rate observed and a levelling off will occur; the 2021 year data (Figure ) may indicate this is underway. The overall decline in NP-likeness of Clinical compounds can be attributable mainly to an increase in aromatic ring count together with a decrease in oxygen atom count. PNPs have introduced more ring system novelty to the clinic versus NonPNPs (Figure ) while having lower NP-likeness (Table ).