The safety and efficacy of America’s medicine supply has long been considered the “gold standard” by which other countries are measured. Our “closed system” comprised of strict regulations for the approval, manufacture and distribution of prescription drugs served us well in an era when those regulations could be enforced. Today, however, a global economy through which goods and services flow virtually unimpeded, and the ever-increasing demand for more accessible and affordable prescription drugs are threatening to overwhelm our regulatory systems and place the medicine supply at risk. The growing presence of substandard, adulterated and counterfeit medicine in the U. S. market is a warning sign that responsible parties need to act promptly to restore the overall integrity of the nation’s prescription drug supply. This will require a holistic approach that employs advanced technology within a comprehensive strategy that includes stakeholder awareness, regulatory enforcement, legal change, and a sustained policy commitment to patient safety and global health.