The health risk of tobacco smoking can best be avoided or reduced by not taking up or quitting the habit. The use of new and innovative tobacco (NTPs, e.g. electronic cigarettes) can either be an aid for smoking cessation or, for those who are not able or willing to quit, an alternative for smoking conventional tobacco products. Before the use of an NTP can be regarded as an effective approach in tobacco harm reduction (THR), the implicated risk has to be evaluated by suitable toxicological methods such as the analysis of the chemical composition as well as assessment of detrimental effects in animal and in vitro studies. In human (clinical) studies, the NTP-related exposure to toxicants and early biological effects can be assessed by the determination of suitable biomarkers. In this review, the suitability of established and newly developed biomarkers of biological effect (BOBEs) for the indicated purpose is evaluated according to five criteria, including the association to diseases, reported difference in BOBE levels between smokers and non-smokers, dose-response relationships, reversibility and kinetics after smoking cessation. Furthermore, the effect size and the resulting sample size required in clinical studies were estimated and considered in the BOBE evaluation process. It is concluded that the rating process presented is useful for selecting BOBEs suitable for risk evaluation of NTPs in clinical and other human studies.