The papers by Robert Berenson and by Steven Lieberman and colleagues show that variations remain a true challenge for those trying to improve the delivery of health care. Recent clarifications in the understanding of unwarranted variations allow us to address variations in a more logical and manageable fashion. In this Perspective we describe key challenges in addressing variations in the context of these recent clarifications. The Centers for Medicare and Medicaid Services (CMS) needs to move forward on information-sharing interventions and use demonstrations to pursue innovative strategies to improve the delivery of care through its purchasing power.