Natural products and their derivatives, including the compounds designed based on the structure of natural product pharmacophores, account for more than 50% of approved drugs. The medicinal value of fungal natural products has been known for centuries, and millions of patients worldwide have been treated with fungal-derived small molecule drugs every year. Fungal-derived small molecule drugs are very valuable, both in terms of market prospects and humanitarian perspectives. This review summarizes the clinical application of fungal natural products, and the development of statins reveals that fungal-derived natural products are an important source of inspiration for drug synthesis in the 21st century. This review covers small molecules of fungal-derived drugs, including natural drugs, related derivatives, and structurally modified drugs.