During President George W. Bush’s tenure in the White House, his administration stood clearly against state-level efforts in California and elsewhere to decriminalize soft drugs. Despite his loyalty to smaller government values and state sovereignty on other issues, the prospect of state-level drug decriminalization led Bush to pursue federal means of enforcing anti-drug laws. Years later, President Barack Obama, though known for his reputation as a federalist, shifted power over drug policy enforcement more towards the state level as a means to allow certain states to enact drug decriminalization policies at their will, particularly with respect to medicinal marijuana. The irony of Bush and Obama’s willingness to turn away from their philosophical views of government control in order to satisfy their personal political preferences regarding drug policy has been largely overlooked and merits scholarly inquiry, particularly at a time when polarizing rhetoric over government involvement in people’s lives has been dominating the political airwaves. In this chapter, I examine this historical irony, the institutional impact of such policy shifts, and how they may shape U.S. drug policy moving forward.