This study focuses on optimum operating strategies for liquid-fed direct methanol fuel cells (DMFCs) to minimize methanol consumption. A mathematical model is developed and verified with experimental data from the literature using the parameter estimation method. The model consists of a set of differential and algebraic equations and makes it possible to describe zero initial hold-up conditions. Based on the model, steady-state simulation results are obtained and explain the dependence on the feed concentration of key variables such as cell voltage, cell power density, overpotentials of both electrodes, and methanol crossover ratio. Dynamic simulation results are also presented to check the transient behaviour of a DMFC operated from start-up to shut-down. Dynamic optimization allows determination of the optimum transient strategies of feed concentration required to maximize the fuel efficiency. With six scenarios of power density load, it is demonstrated that the optimum transient strategies depend heavily on both the load of power density and the number of control actions. The main advantage of these approaches is to reduce fuel consumption and, ultimately, to enable DMFCs to be operated more efficiently.