Methods and systems for selecting a mode for inspection of a specimen are provided. One method includes determining how separable defects of interest (DOIs) and nuisances detected on a specimen are in one or more modes of an inspection subsystem. The separability of the modes for the Dais and nuisances is used to select a subset of the modes for inspection of other specimens of the same type. Other characteristics of the performance of the modes may be used in combination with the separability to select the modes. The subset of modes selected based on the separability may also be an initial subset of modes for which additional analysis is performed to determine the final subset of the modes.