What informs our practice with couples of mixed HIV status? Treating any couple coping with the emotional impact of illness requires sensitivity to a variety of issues related to the past, present, and future of each unique relationship. This chapter begins with a broad overview of those theoretical orientations that have effectively informed the treatment of couples facing a wide array of relationship distresses. The second component provides a comprehensive review and analysis of theoretical approaches that can be employed effectively when treating couples coping with some commonly identified challenges precipitated by a HIV diagnosis.