An apparatus for performing run-to-run control and sampling optimization in a semiconductor manufacturing process includes at least one control module. The control module is operative: to determine a process output and corresponding metrology error associated with an actual metrology for a current processing run in the semiconductor manufacturing process; to determine a predicted process output and corresponding prediction error associated with a virtual metrology for the current processing run; and to control at least one parameter corresponding to a subsequent processing run as a function of the metrology error and the prediction error.