Biosensors often require detecting infinitesimal amount of species, thus their readout must be improved for highest sensitivity and best Signal-to-Noise ratio. We will present a simulation tool for piezoresistive strain sensors, which takes into account nonuniform current flow in e.g., a U-shaped piezoresistor, and calculates local resistivity changes based on the piezoresistive coefficients with corresponding directions. This simulation tool yields DR/R as a result. Thus a real piezoresistor layout, rather than a symbolic resistor, can be simulated. Important aspects of optimum piezoresistive readout for biosensors will be discussed.