Polyene macrolide antibiotics, as effective antifungal agents, are widely used in the treatment of fungal infections, food preservatives and agricultural aspects. With the development of next-generation sequencing technology and bioinformation, numerous antibiotic biosynthetic gene clusters of Streptomyces have been identified. A variety of regulators encoded by regulatory genes play a crucial role in the regulatory network of Streptomyces. This article summarizes the important types of regulatory factors of Streptomyces and reviews the progress of regulatory factors of the biosynthetic gene cluster of polyene macrolide antibiotics. Combining with the functions of regulatory factors, structural binding site and regulatory mechanisms, the potential relationship and research are summarized and prospected.