This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 25 1 / 2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than "S" (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of many recently approved agents, we are able to identify only one de noVo combinatorial compound approved as a drug in this 25 plus year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.It is over nine years since the publication of our first, 1 and three years since the second, 2 analysis of the sources of new and approved drugs for the treatment of human diseases, both of which indicated that natural products continued to play a highly significant role in the drug discovery and development process.That this influence of Nature in one guise or another has continued is shown by inspection of the information given below, where with the advantage of now over 25 years of data, we have been able to refine the system, eliminating a few duplicative entries that crept into the original data sets. In particular, as behooves authors from the National Cancer Institute (NCI), in the specific case of cancer treatments, we have gone back to consult the records of the FDA and added to these, comments from investigators who have informed us over the past two years of compounds that may have been approved in other countries and that were not captured in our earlier searches. These cancer data will be presented as a stand-alone section as well as including the last 25 years of data in the overall discussion.As we mentioned in our 2003 review, 2