The success of new drug discovery in 2021 can be affirmative, although the whole world is still suffering from COVID-19 pandemic. 50 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year. Among them, 27 were defined as first-in-class drugs, accounting for the highest number in the past decade. Notably, small molecule drugs still occupy a dominant position in first-in-class drugs with 15 drugs approved. Some of them were regarded as milestones for the drug discovery including sotorasib, a first small molecular covalent inhibitor targeting the "undruggable" target of the KRAS G12C; asciminib, a first small molecular allosteric inhibitor targeting the allosteric pocket of BCR-ABL1; belzutifan, a first small molecular inhibitor to inhibit HIF-2α; and vericiguat, a first small molecular sGC agonist for the treatment of chronic heart failure (CHF). First-in-class drugs rely on the discovery of novel targets and biological mechanisms, thus requiring different drug design approaches and being important guidance. In this review, we expect to provide research ideas and methods for more first-in-class drugs based on the research background, development process and therapeutic application of 3 first-in-class small molecule drugs in 2021.