Paecilomyces variotii isolated from a broad range of habitats drives the diversification of new high-value-added secondary metabolites that could potentially play an important role in human and animal health. These metabolites include the anhydride metabolite of the nonadride family, as well as the following compounds: naphthopyranone metabolites, sphingofungins, eicosenoic acids, new branched fatty acids, ascofuranone, polyketides, an anacardic acid analogue, straight-chain peptides, and volatile compounds. These natural products show that P. variotii can provide leading compounds for new drug discoveries, which may include herbicide agents, some of which are important in the agrochemical market. Finally, this review outlines recent developments, trends, and prospects for the chemistry of this ascomycete.