Methods for optimizing an aspect of a patterning process based on defects. For example, a method of source and mask optimization of a patterning process includes obtaining a location on a substrate having a threshold probability of having a defect; defining an defect ambit around the location to include a portion of a pattern on the substrate and one or more evaluation points associated with the portion of the pattern; determining a value of a first cost function based on a defect metric associated with the defect; determining a first guide function for the first cost function, wherein the first guide function is associated with a performance metric of the patterning process at the one or more evaluation locations within the defect ambit; and adjusting a source and/or a mask characteristic based on the value of the first cost function, and the first guide function.