With the development of the research on innovative drugs in our country, first-in-class drugs are becoming a main goal for both pharmaceutical companies and scientific institutions. Discovery of first-in-class drugs require amounts of basic research, a massive investment and novel methods, acting as a beacon for the new drug development. In 2020, FDA totally approved 53 novel drugs with 38 small molecules, which still accounting for a major component. Among them, many first-in-class drugs are important including a first EZH2 inhibitor(tazemetostat) for the treatment of epithelioid sarcoma, a first attachment inhibitor(fostemsavir) with novel mechanism for the treatment of HIV, a first farnesyltransferase inhibitor(lonafarnib) for the treatment of HutchinsonGilford progeria syndrome(HGPS) and a first MC4 receptor agonist for the treatment of rare genetic diseases of obesity, etc. The research procedures of the above drugs are representative with new ideas. In this review, we outline3 of the first-in-class drugs to discuss the research background, discovery and development process as well as the therapeutic potentials to provide methods and ideas for the further drug development.