Abstract: Methods and devices are described for calibrating the pressure sensors of a tissue examination device to enable the sensors to produce signals that accurately indicate whether an underlying tissue structure is present in tissue being examined. In general, the calibration is performed using a substance configured to apply a selected amount of pressure to the sensors when engaged in a selected way by the tissue examination device. The sensors are calibrated based on levels of the signals produced in response to the selected amount of pressure imposed by the substance. The tissue examination device may be pressed against the substance, or the substance may be pressed against the sensors. Preferably, the substance applies the selected amount of pressure substantially uniformly to the sensors. A wide variety of substances can be used, such as a foam pad, a rubber pad, a gel, a fluid-containing balloon, and pressurized air.