The revolution of molecular biology in the early 1980s has revealed that biological systems consist of non-linear and stochastic biochemical interactions among many molecules. To understand this complex system, mathematical modeling has been invaluable tools. In this talk, I will introduce the typical process of mathematical modelling including mathematical representation, model fitting to data, analysis and simulations, and experimental validation with an example of circadian rhythms. Across each step of modelling process, I will also describe our efforts to develop new mathematical tools and point to the parts of current tool box of mathematical biology that need further mathematical development.