This chapter focuses on psychophysiological research that measures responses to perceived interpersonal transgressions. The emphasis is on discoveries about internal cognitive, affective, and physiological responses of people who relive interpersonal transgressions and respond in unforgiving and forgiving ways. To account for documented patterns, this chapter views transgressions through a lens of interpersonal expectations about responsibilities within relationships (i.e., accountability). In this view, when people perceive someone’s actions or inactions to be hurtful violations of implicit or explicit expectations for that relationship (e.g., at minimum to “do no harm”), the transgression is painful, disrupts cognitive appraisals, dysregulates emotion, and activates psychophysiological stress responses—not only in victims, but also in transgressors. More studies in this literature focus on the perspectives of victims than of transgressors, and on the peripheral nervous system (especially cardiovascular variables) than the central nervous system, biochemistry, or genetics. Findings show that ruminating about perceived relational wrongdoing activates distressing emotion and stress reactivity, while impairing the regulatory responses of the parasympathetic nervous system, in both victims and transgressors. By contrast, cognitive reappraisals that foster forgiveness toward another person—as well as repentant and accountable forgiveness-seeking and self-forgiveness—activate social connection (e.g., empathy) while regulating emotion and psychophysiology. When forgiving states occur in the context of relational safety and accountability, social disconnection is surmounted, positive emotion is re-engaged, and psychophysiological regulation is restored.