Tobacco taxation is an essential component of a comprehensive tobacco control strategy. However, to fully realize the benefits it is vital to understand the impact of increased taxes among high-risk subpopulations. Are they influenced to the same extent as the general population? Do they need additional measures to influence smoking behavior? The objectives of this study were to synthesize the evidence regarding differential effects of taxation and price on smoking in: youth, young adults, persons of low socio-economic status, with dual diagnoses, heavy/long-term smokers, and Aboriginal people. Using a better practices approach, a knowledge synthesis was conducted using a systematic review of the literature and an expert advisory panel. Experts were involved in developing the study plan, discussing findings, developing policy recommendations, and identifying priorities for future research. Most studies found that raising cigarette prices through increased taxes is a highly effective measure for reducing smoking among youth, young adults, and persons of low socioeconomic status. However, there is a striking lack of evidence about the impact of increasing cigarette prices on smoking behavior in heavy/long-term smokers, persons with a dual diagnosis and Aboriginals. Given their high prevalence of smoking, urgent attention is needed to develop effective policies for the six subpopulations reviewed. These findings will be of value to policy-makers and researchers in their efforts to improve the effectiveness of tobacco control measures, especially with subpopulations at most risk. Although specific studies are needed, tobacco taxation is a key policy measure for driving success.