The globalization of tobacco began more than 500 years ago, but the public health response to the death, disease, and economic disruption that it has caused is fewer than 50 years old. In this report, the authors briefly trace the history of tobacco use and commerce as it moved from the Americas in the late 15th century and then eastward. They then discuss the wide range of issues that must be addressed, and the equally wide range of expertise that is needed if the global health community is to be successful in reducing, and eventually eliminating, the rising tide of tobacco use, particularly in the low- and middle-income nations that are the target of the multinational tobacco industry. CA Cancer J Clin 2010;60:50–61. © 2010 American Cancer Society, Inc.