Fungi are devoid of advanced immune system, but have evolved to rely on secondary metabolites as defense mechanism (antibiotics) against predators, parasites. Many fungal secondary metabolites have been widely used in industry and medicine. At the beginning of the 21st century, more than 10 of the 20 most profitable products used in medicine are of fungal origin. Despites the exploratory efforts in medicine and industry, our knowledge about such natural product is still limited. There is a wide range of undiscovered secondary metabolites that may have direct impacts on drug discovery, or as an inspiration for unnatural product. The genes for the synthesis of secondary metabolites are found clustered together and their expression appears to be induced by one or a few global regulators. The objective of this study is to use Fusarium species as a model to understand the evolution and diversity of such gene clusters. The fungal species within genus Fusarium have evolved extraordinary chemical diversity and produce highly complex and biologically active secondary metabolites. Employing the power of comparative genomics, we have identified potential secondary metabolite producing gene clusters in the four sequenced Fusarium genomes. Only small fraction of the identified clusters was shared, while many are species specific. Some of the gene clusters have been directly connected with known secondary metabolites, while majority with unknown functions. Gene expression analysis confirmed the co-regulation of some clusters under certain growth conditions. The evolution of the gene clusters and the functional implication of such study will be discussed.