To indicate the importance of fungal enzyme inhibitors (FEI) it is only required to mention penicillin. However, many other natural products from fungi have been described. Combinatorial chemistry (CC) is not providing the medicines that were predicted and it is time to return to natural products (NP). The inhibitions of enzymes by FEI run the gamut of medicinal applications and toxicity. The field is, or should be, “big science”, although many areas are underfunded partly from an overemphasis of CC, and from ignorance of fungi as a whole. Furthermore, the use of PCR with fungi is growing exponentially, without regard to adequate controls because of FEI. This leads to false negative results (FNR) which is the worst possible outcome in diagnostic mycology. The field of mycotoxin research is huge and related to NP discovery. Much of the toxicity relates to FEI. In terms of therapeutics, the fungal compounds can be used against cancer, diabetes, poisonings, Alzheimers disease, etc. The forms of inhibitions include acetylcholinesterase, nuclear factor- kappa B, protein kinase, tyrosine kinase, aromatase and sulphatase, matrix metalloproteinases, cyclooxygenase, DNA polymerase/topoisomerases, glycosidases and more. Endophytic fungi may be sources of undetected compounds. Fungi can also transform precursors into potential inhibitors. The time is right for a review in the field of FEI.