Fungus, the heterotrophic thallophytes, along with bacteria and plants, produces a vast range of secondary metabolites that might be beneficial antibiotics, pharmaceuticals, or harmful toxins. The genes for primary metabolites remain dispersed throughout the fungal genome, whereas genes encoding secondary metabolites, also known as secondary metabolomes, like bacterial secondary metabolite operons are found to be arranged in clusters. The fungal secondary metabolites belong to the chemical categories of polyketides, nonribosomal peptides, terpenes, and indole alkaloids, having a specific backbone enzyme associated with concomitant clusters, including polyketide synthases, nonribosomal peptide synthetases, terpene cyclases/synthase, and prenylation synthetases, respectively. The regulation of biosynthetic genes associated with a particular cluster has been carried out by pathway-specific transcription factors for which the encoding gene might not be part of that cluster. The abiotic concerns like carbon, nitrogen, and pH have a role in the expression of these transcription factors and thus in regulation of gene clusters. The production of spores and secondary metabolites in several fungus species is a coupled process regulated by G-protein signal-transduction pathways. Recent studies also suggest coregulation of several gene clusters simultaneously through the event of chromatin reorganization. The evolutionary events like gene duplication and horizontal gene transfer are proposed mechanisms in the evolution of biosynthetic gene clusters and have higher frequencies in clustered genes in contrast to nonclustered counterparts. © 2020 Elsevier B.V. All rights reserved.