A misregistration measurement and region of interest selection system (MMRSS) for measuring misregistration between at least two layers on a wafer in the manufacture of semiconductor devices, the MMRSS including a set of misregistration metrology tools, including at least two misregistration metrology tools, and a misregistration analysis and region of interest selection engine operative to: analyze a plurality of misregistration measurement data sets associated with a set of regions of interest (ROIs) of at least one measurement site on the wafer and at least partially generated by at least one first misregistration metrology tool, and wherein each of the data sets is associated with a set of quality metrics, identify a recommended ROI and communicate the recommended ROI to at least one second misregistration metrology tool of the set of misregistration metrology tools, the second misregistration metrology tool being operative to generate misregistration metrology data associated with the recommended ROI.