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The development of lab-on-a-chip systems has moved from the demonstration of individual components to a complex assembly of components. Due to the increased complexities associated with model setup and computational time requirements, current design approaches using spatial and time-resolved multiphysics modeling, though viable for component-level characterization, become unaffordable for system-level design. To overcome these limitations, we present models for the system-level simulation of fluid flow, electric field, and analyte dispersion in microfluidic devices. Compact models are used to compute the flow (pressure driven and electroosmotic) and are based on the integral formulation of the mass, momentum, and current conservation equations. An analytical model based on the method-of-moments approach has been developed to characterize the dispersion induced by combined pressure and electrokinetic-driven flow. The methodology has been validated against detailed three-dimensional (3-D) simulations and has been used to analyze hydrostatic-pressure effects in electrophoretic separation chips. A 100-fold improvement in the computational time without significantly compromising the accuracy (error less than 10%) has been demonstrated.