Global interdependence was supposed to herald a new age of peaceful cooperation. America's global leadership in many ways derives from its ability to maintain, augment, and protect mutually advantageous interactions. Yet the United States has also tried to use its dominance in networks of finance, trade, and communications as a tool of coercion. No region has been more affected by such weaponized interdependence (WI) than the Middle East. But WI, enacted through various forms of direct and indirect sanctions and embargoes, has a spotty record of success. WI is typically coupled with military force and usually targeted against isolated and weak opponents. WI has contributed to several of the region's gravest humanitarian crises, including Iraq in the 1990s and Yemen since 2014. This has cost the United States support from regional states and from the proverbial “street.” Moreover, targets often find ways to upgrade and deepen their repression as they adapt to network restrictions. The United States must be prudent in selecting targets for WI sanctions, broader in recruiting allies for its WI campaigns, and transparent about the humanitarian costs that WI imposes.