A medical reference and registration system includes a substrate configured for placement on an external surface of a patient such that the substrate conforms to and moves with the external surface of the patient. The medical reference and registration system also includes multiple integrated sensor-fiducial marker devices mounted on the substrate. Each integrated sensor-fiducial marker device includes a sensor and at least one fiducial marker coupled to the sensor. Each sensor is pre-aligned with respect to the at least one fiducial marker so that a location of each fiducial marker is known with respect to its respective sensor.