Flexizymes are de novo ribozymes capable of charging a wide variety of non-natural amino acids on tRNAs. The flexizyme system enables reprogramming of the genetic code by reassigning the codons that are generally assigned to natural amino acids to non-natural residues, and thus mRNA-directed synthesis of non-natural polypeptides can be achieved. In this review, we comprehensively summarize the history of the flexizyme system and its subsequent development into a practical tool. Furthermore, applications to the synthesis of novel biopolymers via genetic code reprogramming and perspectives for future applications are described.