Abstract: This paper discusses the innovation methods of all the Nobel Prize Laureates in Chemistry. It shows that the Nobel Prize Laureates with scientific realism from different angles of view have different opinions on the relationship between theory and experiment. The ontology and concepts of chemistry had changed along with the innovation of scientific equipments. The innovation methods of all the Nobel Prize Laureates present three periods. Firstly, physical models and instruments were introduced to chemistry research, and the chemists focused on the simplified experiments. Secondly, the research of valence and structural problems and chemical kinetics were dealt with newly scientific equipments. Thirdly, computational approach of quantum chemistry was more often used by chemists. Molecular basis of biological phenomena was studied in terms of structure and function.