Smoking remains the leading preventable cause of death and disease in the US. While e-cigarettes (EC) are undeniably harmful when used by adolescents and nonsmokers, the perpetuation of the increasing negative perceptions of EC and widespread false belief that EC are equal or more harmful than combustible cigarettes (CC) represents a significant missed public health opportunity. EC have great potential to serve as a mechanism for smoking harm reduction among hard-to-treat populations of smokers who have failed to quit with currently available treatments. In this paper, we outline why we need to overcome the hostile EC research environment to explore the potential use of EC as a harm-reduction strategy in hard-to-treat populations.