ISO 50001:2011 is a voluntary international standard that provides a flexible framework for implementing a continual improvement-based system to manage energy. Experience shows that institutionalizing ISO 50001’s proven best practices can lead to deep total energy savings of 5–20 percent annually. Based on an internationally developed methodology for predicting future impacts of ISO 50001 uptake within a region from McKane et al. (2017), we estimate that adopting ISO 50001 within the U.S. commercial buildings sector can generate annual energy savings of approximately 65 billion Btu in 2030. Commercial properties also could leverage ISO 50001 to unlock benefits through increased property values, rental premiums, company valuations, and access to new capital markets. Currently, within the United States, ISO 50001 has been primarily adopted in the industrial sector, with limited uptake in the commercial sector. This paper discusses the motivation, implementation approach, and achieved benefits of two ISO 50001-certified companies with commercial building portfolios in the United States. Anecdotal results from these companies show that the commercial buildings sector has an opportunity to implement ISO 50001 cost-effectively at the enterprise level and scale energy savings quickly—especially among organizations with campuses and/or chains of geographically scattered buildings with similar building energy systems. These early results, coupled with estimated impacts from ISO 50001 uptake within the U.S. commercial buildings sector, suggest that direct uptake and incorporation of the standard in utility and government programs will generate significant energy and greenhouse gas reductions.