The United States is witnessing a transformation of Central Asia—a critical yet highly understudied and misunderstood area of the world, which is seeing growing influence of China, India, and Russia. The agendas of these actors, as well as the United States, Japan, the EU, Turkey, and Iran, among others, have enabled Central and South Asian countries to shrink their connectivity gaps dramatically in the last 2 decades, aiding the U.S. grand strategy of advancing global connectivity. However, they could also potentially undermine a multidirectional connectivity and limit development choices for the Central Asian states, generating challenges and opportunities for the United States, whose global influence is receding. The U.S. future global and regional role and capabilities will depend on how well Washington adjusts its grand strategy in response to current and projected economic and geopolitical trends in the era of rising powers. As the United States calibrates its ends and means, its assessment of the importance of Central and South Asia for its strategy will in large part hinge on security trends unfolding in Afghanistan and Pakistan. Whether Central Asia will become a major pillar of the U.S. grand strategy, given the rise of China and India and the resurgence of Russia, remains unclear. But its goals of supporting sovereignty, democratization, and inter-regional links in Central and South Asia offer some hope that Washington will continue to support the region’s global connectivity, preferably by pursuing an engaged, long-term, and substantive regional strategy.