Determining the proportion of avoidable disease burden attributable to substance use is important for both policy development and intervention implementation. Current epidemiological theory has in principle provided a method to estimate avoidable burden of disease and the available statistical tools can provide first rough estimates. The method described in this paper, and its statistical procedures, are exemplified to estimate avoidable burden of tobacco-related disease in Canada. However, further effort is needed to find solutions in the methodological details, namely exposure measurement, risk factor multidimensionality, estimation of changes in exposure distribution over time, and estimation of risk relationships from multiple exposures changing over time with multiple endpoints (causal webs). The impetus to begin refining methods to obtain better starting points for estimating avoidable burden of disease is obvious and should be carried through in order to see real changes through evidence-based policy and intervention.