The activation of pepsinogen to pepsin was investigated by a combination of experiments and computations. An algorithm was at first made for the present study. According to the established algorithm, experiments and computations were performed. In the experiments, the spectral changes in the early stage of the activation were measured by stopped flow technique, and the changes in the amounts of pepsinogen and pepsin during the activation were followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Furthermore, the sensitivity of the molecular species involved in the activation process to alkaline solution was measured to characterize intermediate components. The time-course in the early stage exhibited an exponential profile. The existences of dimeric intermediate and the other intermediates were evidenced by gel electrophoresis and alkali treatment, respectively. The activation process showed the dependence to the initial concentration of pepsinogen, indicating that the activation process is essentially nonlinear reaction. Computer simulations were performed with many postulated basic schemes, and Scheme 8 was eventually selected as the most reasonable one. In Scheme 8, the first step is a conformational change with a rate constant k1 which is a function of the first power of hydrogen ion concentration of the medium. The second step consists of two steps; an intramolecular (or unimolecular) reaction accompanied with the release of peptides and an intermolecular (or bimolecular) reaction in which X2 and X3 combine mutually into dimeric intermediate X5_ X5 cleaves to two molecules of X3 with releasing the peptides. The third step is reversible one with pK 3.1. The conversion of X3 to X4 is accompanied with the spectral change and the uptake of hydrogen ion from the medium. X3 and X4 are conformational isomers, and have same molecular weight. They exhibit the same peptic activity in acidic medium.