An ongoing conversation in the Information Systems literature addresses the concern, "How can we conduct research that makes a difference?" A shortage of high-impact research will, over time, challenge the identity and weaken the viability of IS as an academic discipline. This paper presents the systematic high-impact research model (SHIR), an approach to conducting high-impact research. SHIR embodies the insight gained from three streams of high-impact research programs spanning more than 50 years. The SHIR framework rests on the proposition that IS researchers can produce higher-impact contributions by developing long-term research programs around major real-world issues, as opposed to ad hoc projects addressing a small piece of a large problem. These persistent research programs focus on addressing the entirety of an issue, by leveraging multidisciplinary, multiuniversity research centers that employ a breadth of research methods and large-scale projects. To function effectively, SHIR programs must be sustained by academic and practitioner partnerships, research centers, and outreach activities. We argue that SHIR research programs increase the likelihood of high impact research.