As a result of the devastating impact of the opioid epidemic, increased numbers of children are being raised by their grandparents in what are known as grandfamilies. Despite these children and their families experiencing difficult environmental circumstances, numerous adverse life events, and challenging family dynamics, empirical examinations of the opioid epidemic, as it relates to grandfamilies, remain limited. The purpose of this review is to advance the understanding of how grandfamilies have been impacted by the opioid epidemic by using a systemic perspective to highlight themes and major conclusions within the existing conceptual and empirical literature. The review reveals five systemically informed themes including the assumption of caregiving responsibilities, grandparent stress and well-being, caring for vulnerable grandchildren, navigating relationships with parents, and contextual stressors of societal stigma and barriers to service. To extend this work, systemically informed recommendations for clinical intervention and future priorities for research and policy are discussed.