Abstract: Biomacromolecular drugs have been recognized as the most promising field of drug research and development in the 21st century; however, their mode of delivery is too simple, making it difficult to meet the clinical therapeutic requirements. As a novel transdermal drug delivery system, microneedles can directly penetrate the stratum corneum and deliver drugs to the skin tissues for absorption, with the advantages of painlessness, high efficiency and high safety in delivery. In recent years, more and more studies have been conducted on the microneedle-mediated transdermal delivery of biomacromolecular drugs such as proteins, peptides, nucleic acids, and vaccines, and great progress has been made in theory and technology. This review summarizes the application of biomacromolecular drugs delivered by microneedles in the treatment of such major threats as infectious diseases, diabetes and tumor, and analyzes the technological bottlenecks involved in their practical application and clinical translation, with an outlook on the future development of microneedle technology, in the hope of providing some insight for the development and clinical translation of microneedle-mediated delivery of biomacromolecular drugs.