We have developed the fungal artificial chromosome [FAC, or autonomously replicating E. coli-fungal shuttle bacterial artificial chromosome (BAC)] technology. The FAC system or technology enables unbiased capturing of 263 full-length large secondary metabolite (SM) gene clusters (each lOOkb or larger) as individual FAC clones, from 6 sequenced fungal genomes for one-step transformation and heterologous expression. The FAC technology also enables precise SM gene and gene cluster editing and activating silent and cryptic SM gene clusters. We have demonstrated that the FAC technology is extremely effective for natural product and drug discovery by using a liquid chromatography-fourier transform mass spectrometer (LC-FTMS) with novel data analysis pipeline. This novel FAC platform provides a major advance in the study of fungal biosynthesis, enabling rapid detection of novel SMs, identification of their biosynthetic machinery, and dissection of their biosynthesis. As an example, three SM compounds: benzomalvin A, ophiobolin G, and a novel lipopeptide has been discovered from a FAC clone: AtFAC9J20 containing a super-SM gene cluster. This disruptive technology could revive natural product and drug discovery platform from sequenced fungi, fungal metagenomes and environmental microbial metagenomes.