Folding of some proteins in prokaryote, eukaryote and virus is contrary to Anfinsen’s dogma: Their structure is not determined by the protein’s amino acid sequence. However, the proper folding of them requires the assistance of intramolecular chaperone (IMC). On the basis of different mechanism, IMC can be classified into two categories. The type Ⅰ IMC assists the tertiary structure formation, and the type Ⅱ IMC guides the assembly of quaternary structure to form the functional protein complex. IMC guides the protein folding more effectively than molecular chaperone. This mechanism is a better strategy for protein folding. Study on IMC mechanism not only can determine the essential residues on the guidance of mature peptide folding, but also can modify these residues to change mature peptide. This is a novel approach of protein engineering.