A defect inspection system includes an inspection sub-system and a controller communicatively coupled to the detector. The inspection sub-system includes an illumination source configured to generate a beam of illumination, a set of illumination optics to direct the beam of illumination to a sample, and a detector configured to collect illumination emanating from the sample. The controller includes a memory device and one or more processors configured to execute program instructions. The controller is configured to determine one or more target patterns corresponding to one or more features on the sample, define one or more care areas on the sample based on the one or more target patterns and design data of the sample stored within the memory device of the controller, and identify one or more defects within the one or more care areas of the sample based on the illumination collected by the detector.