Advances in information and communication technologies shape consumers' attitudes towards engagement in their own health and their interface with the health-care system. The use of eHealth tools holds promise for supporting and enabling health behaviour change and the prevention and management of chronic diseases. The authors review issues related to study design, treatment implementation, and outcome measurement in eHealth trials, providing examples from the literature and from their own ongoing studies. Selection of a comparison group and design considerations related to participant preferences are based on the state of the science and current practice in the particular field. Randomized designs allow for control of selection bias and are favoured in both efficacy and effectiveness trials of eHealth interventions. Depending on the choice of comparison groups, eHealth applications must be fairly robust to demonstrate their efficacy above and beyond active controls. Strategies to ensure treatment fidelity and ongoing participant engagement can be challenging and are not always successful. Patient-reported outcomes are common to eHealth studies. Other outcomes, such as the costs associated with new eHealth applications, are equally if not more important for decision-makers. This discussion is intended to inform future trials and thereby serve to advance the science of eHealth.