Methods and systems for detecting defects on a wafer using defect-specific and multi-channel information are provided. One method includes acquiring information for a target on a wafer. The target includes a pattern of interest (POI) formed on the wafer and a known defect of interest (DOI) occurring proximate to or in the POI. The method also includes detecting the known DOI in target candidates by identifying potential DOI locations based on images of the target candidates acquired by a first channel of an inspection system and applying one or more detection parameters to images of the potential DOI locations acquired by a second channel of the inspection system. Therefore, the image(s) used for locating potential DOI locations and the image(s) used for detecting defects can be different.