Waterpipe tobacco usage is spreading rapidly worldwide, with reports of more youth being waterpipe users compared to adults. In many areas of the world, waterpipe usage surpasses cigarette smoking. Waterpipes and cigarettes are both mechanisms for inhalation of tobacco smoke and therefore have serious health consequences. However, because of the many differences between the two products, prevention and control strategies that have proven effective for cigarettes may not transfer readily to waterpipe. This report highlights the differences between waterpipes and cigarettes in toxicant exposure and physiologic effects, patterns of use, social norms, the extent of evidence, and the policy environment. There is little evidence to date around effective interventions for waterpipe prevention and control. The current state of evidence for intervention to curb or control waterpipe is at ground zero and critically needs attention from both scientists and policy makers. National and global efforts aimed at cigarette prevention have succeeded, particularly in developed countries. We suggest the time has come to harness what we know works for cigarette prevention and control and adapt it to tackle the growing epidemic of waterpipe tobacco use.