The electronic cigarette (e-cigarette) has been regarded by many as a healthier alternative to the combustible cigarette, yet there is a lack of consensus concerning the health consequences and the health benefits associated with e-cigarette use. We review the research on the effects of e-cigarettes on multiple physiological systems, examine the association between e-cigarette use and combustible cigarette uptake and cessation, and highlight research necessary to build consensus. Although the levels of known toxicants and carcinogens tend to be significantly lower in e-cigarettes than in combustible cigarette smoke, toxicants in e-cigarette e-liquid and those that form as part of the vaporization process may produce adverse health consequences in their own right. Acute effects have been noted in the pulmonary, cardiovascular, and immune systems, which highlight the need for research on long-term exposure. The specific chemical constituents and the levels of those constituents that pose harm remain largely uncharacterized. In addition, the efficacy of e-cigarettes for smoking cessation has yet to be established. As the e-cigarette has evolved rapidly, so has the methodology across studies, making cross-study comparisons more difficult to synthesize. The latest generation of e-cigarette devices deliver nicotine and toxicants at higher levels than earlier devices, especially in experienced users. E-cigarettes pose a risk for nicotine exposure, dependence, and combustible cigarette uptake. E-cigarettes and their delivered toxicants appear harmful to multiple organ systems, although the current body of evidence is limited, especially in terms of long-term effects. Further research is warranted with a focus on individual devices, e-liquid constituents, user characteristics, and patterns of use. Any potential benefit of e-cigarettes for smoking cessation must be weighed against the risks. Given the potential longer-term effects, efforts to prevent e-cigarette use in youth are critical.