Abstract: Systems and methods for positioning a multi-featured biological array relative to a signal acquisition device. Detection of the array's positional deviation may be achieved by a calibration beam reflected from the array surface and detected by a position sensitive detector (PSD). The PSD-measured positional deviation can be transformed and used in a control loop to correct for positional variations of the array. The calibration beam and PSD may also be used to detect the array or feature boundaries, thereby allowing lateral centering or positioning of the array relative to the signal acquisition device.