In the absence of an ethical, practical, and economical randomized trial, the epidemiologist is left to explore other methods in efforts to assert causality. An approach based on genotypic variation has the potential to mitigate against some of the problems found within conventional observational studies. Genetic variations associated with risk factors of interest at the population level can be used as proxy measures for these risk factors and to generate estimates of causal effect. The potential and the possible limitations of this approach within the cardiovascular field are presented in this review.