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This systematic review critically evaluates 21 grandparent-focused prevention programs designed to benefit grandparent caregivers or target grandparent caregivers as agents of change for grandchild development. These grandparent programs were published in 35 peer-reviewed articles in the last 31 years. For each program, we described the phase of development of program (i.e., feasibility, pilot, and efficacy), delivery characteristics, and adaptations of existing evidence-based programs to meet the needs of grandparent caregivers in diverse sociocultural backgrounds. For programs tested under a controlled trial design, we evaluated core components and preliminary effects on targeted outcomes. Most studies targeted grandparents who served as primary or custodial caregivers in the USA, while limited studies targeted supplementary grandparent caregivers. Thirteen programs which were evaluated using pretest–posttest designs demonstrated feasibility and acceptability of the grandparent programs. Moreover, eight programs which were evaluated using randomized-controlled trials (RCTs; 5 pilot and 3 full-scale efficacy trials) demonstrated promising outcomes. Additionally, we identified six core components and 17 specific elements in eight programs evaluated using RCT designs. Overall, we provide a comprehensive critique of this body of literature as well as directions for future studies, including the need to develop programing tailored to grandparent caregivers with unique needs. [ABSTRACT FROM AUTHOR]