Borderline personality disorder has been estimated to occur among about 4% of those with autism spectrum disorder. This co-occurrence can escalate the challenges of treating either condition separately, and patients often face severe challenges in psychosocial and occupational functioning. Clinicians need guidance to manage a high degree of complexity, using standards of care and a synthesis of what is known so far, to navigate the currently limited armamentarium of clinical tools. This article reviews the available scientific research and clinical experience with respect to diagnosis, psychoeducation, treatment framework, safety management, other co-occurring disorders, and multimodal treatments. It also discusses future directions for generating new knowledge to improve the care of patients with this important co-occurrence. Although the discussion explores the unique complexity and relative lack of clinical guidelines at present, good psychiatric management serves as a clinical framework that anchors treatment approaches as the evidence base develops.