The membrane microseparator is a milliliter-scale flow chemistry module that continuously separates a biphasic flow through a PTFE microporous membrane. It has found a wide range of applications in the continuous manufacturing of active pharmaceutical ingredients and fine chemicals, especially those involving multiple synthetic steps. Yet, the accurate prediction and control of the pressure balance needed for successful phase separations is technically challenging. In this article, we present systematic modeling of the operating ranges of the membrane microseparator. We characterize the retention and breakthrough phenomena of the device and develop two new analytic models for retention and breakthrough by taking into consideration the tortuosity factor and pore size distribution. The new models are shown to be better predictors of the experimental results than the original theoretical models based on the simple Young-Laplace equation and the straight-channel Hagen-Poiseuille equation.