This chapter examines the role of neurobiological mechanisms in understanding NSSI, with a particular focus on research and clinical implications. An overview of research on emotion regulation, pain, the stress response, and social stress are reviewed for NSSI, including those with and without borderline personality disorder. Although research on the neurobiological processes involved in NSSI is just beginning, the field has progressed rapidly in the last 10–15 years. For example, there is evidence to suggest that individuals with NSSI show an altered stress response, which seems especially pronounced in response to interpersonal stressors. Additional research is needed, however, especially more sophisticated and longitudinal designs to examine if neurobiological vulnerability, especially in response to adverse life events, exists prior to initiation of NSSI.