Responding to stimuli as same and different can be considered a critical component of a variety of language and academic repertoires. Whereas responding to “sameness” and generalized identity matching (i.e., coordination) have been studied extensively, there appears to be a significant gap in behavior analytic research and educational programs with regard to nonmatching relations or relations of difference. We review research on difference relations from a variety of domains, including comparative psychology, as well as experimental, and translational behavior analysis. We examine a range of studies, including research on the perception of difference and oddity responding, as well as investigations on establishing relational frames of distinction. We present suggestions for future research and describe potential methods for teaching skills related to relations of difference.